Harris was born in Plainview, New York and was raised by her mother Fran, along with one sister, Ashley. Harris is Jewish. While living in Florida during elementary school, Harris won a beauty contest, winning a trip to New York City for ten days. While there, she was offered various modeling jobs, but turned them down because they were all far from her home. Her mother was eventually transferred back to New York due to her job and Harris began work as a model. She began appearing in television commercials, too.
In 1985, at age seven, Harris was cast in the role of Samantha "Sammi" Garretson in the ABC soap opera One Life to Live, and she stayed on the program for three years. Her character was considered a "miracle child", extracted as an embryo from the womb of her deceased mother and implanted in a family friend, whom her father later married. In 1987, Harris made an appearance in the series Spenser: For Hire, portraying a girl named Tara.
Following her early television work, Harris successfully auditioned for the role of Jamie Lloyd from the fourth edition of the Halloween franchise, beating out several other young actresses, Melissa Joan Hart among them. Harris celebrated her eleventh birthday on set. Halloween 4: The Return of Michael Myers was released in October 1988 to critical and commercial success. It went on to gross over $17 million worldwide, $6,831,250 in its opening weekend alone. On doing this type of film at such a young age, Harris stated:
"It was fun for me. I knew we were making a movie and I knew that it was make believe. I was more worried about being a good, little actress and being able to cry and scream really good. I think everybody made such an amazing effort to make sure that I knew that it wasn't real. In between takes we would joke around and it was just fun. It didn't really bother me until I got to be older."
Harris returned the following year for the sequel, titled Halloween 5: The Revenge of Michael Myers, which was not as successful as its predecessor. Harris portrayed Jamie Lloyd once again, but her character was mute for the first half of Halloween 5 owing to events in the previous film.
In 1990, Harris appeared in her third film, Marked for Death, as protagonist John Hatcher (Steven Seagal)'s niece Tracey. The action film had a $12 million budget and earned $43 million domestically and $57 million worldwide. It has a 22% approval rating at Rotten Tomatoes, and Entertainment Weekly gave it a letter grade of "C". 1991 saw Harris partake in several film and television projects, including the made-for-television films Don't Touch My Daughter, as a young girl who is kidnapped and molested, and The Killing Mind, where she portrayed main character Isobel as a child. Later that year, Harris made an appearance on the sketch-oriented show In Living Color.
Harris' next major role was in the 1991 comedy film Don't Tell Mom the Babysitter's Dead, as Melissa Crandell, with the story revolving around five siblings whose mother goes to Australia for two months, only to have her children's babysitter die. The young protagonists choose not to tell their mother and attempt to live on their own. The film has a 31% approval rate on Rotten Tomatoes. Harris had a guest role in the 1991 series Eerie, Indiana, portraying a character who receives a heart transplant then begins to act like the heart's original owner. She also guest starred in an episode of Growing Pains, as Susie Maxwell. Harris had the role of Darian Hallenbeck in the 1991 action film The Last Boy Scout, alongside Bruce Willis and Damon Wayans. The film grossed $7,923,669 in its opening weekend, and the total gross was $59,509,925. Reviews were mixed, and some critics cited the Christmastime release for such a violent film as a reason for its somewhat underwhelming box office.
During the next few years, Harris mostly participated in television projects rather than feature films. She had a part in the Pilot for the potential CBS series 1775, although it was not picked up. Starting in 1992, Harris had the recurring role of Molly Tilden on the sitcom Roseanne, then joined Roseanne Barr again for the made-for-Television film The Woman Who Loved Elvis, this time as daughter Priscilla. She appeared in an episode of Jack's Place the same year, portraying a young woman named Jennifer. A notable theatrical film role was that of Gwenie in 1993's Free Willy, which had a US gross of $7,868,829 in its opening weekend and went on to make $77,698,625 in the US and $153,698,625 worldwide. In 1994, she appeared on the drama series The Commish, playing the role of Sheri Fisher for one episode. The same year, Harris portrayed the main character's daughter Jessica in the television film Roseanne: An Unauthorized Biography, based upon her former co-star Roseanne Barr. Also in 1994, Harris guest starred in the sitcom Boy Meets World.
In 1995, Harris learned that producers of then-upcoming Halloween: The Curse of Michael Myers were looking for another actress to play the role originally portrayed by her, Jamie Lloyd, as they wanted someone over the age of 18. Only 17 at the time, Harris got emancipated in order to appear in the film, yet she was not happy with the fate of her character in the script, who was killed early into the proceedings, and was also dissatisfied with the salary she was offered as it did not even cover the cost of her emancipation. She ultimately abstained from reprising her role and was replaced by J. C. Brandy. Harris has since admitted to being glad she did not rejoin the series at this point, believing that this allowed her to make her later return in the 2007 remake of the original Halloween. Still, Harris can be seen in versions of Curse that include the previous film's ending.
In 1996, Harris shared two characters with Katherine Heigl for the made-for-television film Wish Upon a Star: Harris played Hayley Wheaton, a nerdy girl who switches bodies with her older, more popular sister Alexia (Heigl). Also in 1996, Harris starred in the films Shattered Image and Back to Back, and, the same year, she had the role of young survivor Ashley Crighton in Daylight, the disaster film toplined by Sylvester Stallone. While Daylight has a 26% approval rating on Rotten Tomatoes and grossed $33 million in the United States, it took in over $126 million overseas, resulting in gross earnings of $159,212,469 worldwide. In 1997, Harris appeared in two episodes of the medical drama ER as Laura Quentin. In 1998, Harris had the lead role of Lulu in the film Dizzyland, where she portrayed a sexually abused teenager, and also appeared in an episode of Diagnosis: Murder. She then appeared in the popular slasher Urban Legend, her first horror film since her early Halloween credits. She portrayed Tosh, a goth girl who is murdered while her roommate (protagonist Alicia Witt) is resting on the other side of the room.
Beginning in 1998, Harris was among the main cast of Nickelodeon's animated children's series The Wild Thornberrys, chosen to voice Debbie Thornberry, the sister of a girl who can talk to animals. The protagonist, Eliza, travels the world with her family and uses her special ability to help the animals. The series lasted for five seasons, with a total of 92 episodes airing between 1998 and 2004. It spawned the television film The Origin of Donnie in 2001 and the 2002 theatrical release of The Wild Thornberrys Movie, which grossed $40,108,697 in the US. Another film, Rugrats Go Wild, dealt with the Thornberrys meeting the characters from the popular series Rugrats. Released in 2003, it opened at #4 at the box office and grossed $39 million in the US, about the same as the Thornberrys Movie. The last episode of the Thornberrys' fifth season and series finale aired in 2004.
Harris continued to make film and television appearances while doing The Wild Thornberrys. She portrayed a teenage witch named Aviva in a 1998 episode of Charmed, starred in the 1999 film Goosed as protagonist Jennifer Tilly's younger self, and appeared as Justine in the television film Hard Time: Hostage Hotel. She had a supporting role in the crime and comedy film Poor White Trash come 2000, and went on to star in the 2001 comedy Killer Bud. Between 2000 and 2002, Harris was a cast member of the series That's Life. Her character, Plum Wilkinson, featured in all but eight episodes and was involved in a romantic relationship with Kevin Dillon. Harris later appeared in an episode of The West Wing, had a supporting role as Leila in the 2003 television film The Partners and was in the theatrically released films Debating Robert Lee and Em & Me (both 2004). From 2004 to 2005, Harris was a main cast member of the computer-animated sitcom Father of the Pride, appearing in all 14 episodes.
In January 2007, it was revealed that Harris had been cast as Annie Brackett in the remake of horror landmark Halloween. This marked Harris' first participation in the Halloween franchise since The Revenge of Michael Myers eighteen years prior. The remake, also called Halloween and directed by Rob Zombie, featured actors such as Scout Taylor-Compton and Malcolm McDowell. Harris has revealed that Zombie wanted no one from previous Halloweens in the film, but, once she auditioned, he changed his mind. The film, which cost $15 million to make, went on to gross $80,253,908 worldwide, making it the highest-grossing film in the Halloween franchise in unadjusted U.S. dollars. Unlike in the original version, Annie Brackett survives, despite Michael Myers (Tyler Mane)'s goal to torture her to death. Annie encounters her stalker in a short skirt, having her shirt off, which marked Harris' first nude appearance. She stated "[It] is something that I wanted to do because everyone's like, 'Oh, she's little Jamie. She's 14.' And it's like, no, actually, I'm 30. It's something that I've never done before." Harris admits that she kept her chest exposed while the cameras were not rolling, preparing to portray Annie at her most vulnerable. On facing off against Michael Myers once again and at the same time having her first nude scene, she also commented:
"I had a harder time emotionally with Rob Zombie's Halloween and H2 than I did when I was a kid. When I was a kid, it was totally fun and I didn't understand when I did Rob's Halloween, why it was so hard for me to shake it off. I'm like, "I'm an actress! Why am I getting a feeling like I want to cry? This is weird! I did enough crying when I was there [on set]. I don't know why I'm still feeling this way". I think it was because it was the first time I was ever physically touched by him. As a little girl, as Jamie, he never got me, ever. Now as an adult, I don't have my clothes on, doing scenes I've never done before as an actor, and I'm actually being attacked. Even though I should know the guy by now, it's still a weird thing that happens with your psyche I think."
The same year, Harris starred in the also Halloween-themed Left for Dead. For Fearnet, she hosted Route 666: America's Scariest Home Haunts. 2009 saw her in a leading role in Blood Night: The Legend of Mary Hatchet, as Felicia Freeze in the comedic superhero film Super Capers and alongside Robert Patrick in The Black Waters of Echo's Pond. Fear Clinic, a Fearnet original web series featuring Harris as well as Robert Englund and Kane Hodder, made its debut the week of Halloween 2009. Also in 2009, Harris reprised her role of Annie Brackett in the sequel Halloween II. Halloween II was officially released on August 28, 2009 in North America, and was met with negative reception from most critics. On October 30, 2009 it was re-released in North America to coincide with the Halloween holiday weekend. The original opening of the film grossed less than that of the 2007 remake, with approximately $7 million. The film would go on to earn $33,392,973 in North America and $5,925,616 in foreign countries, giving Halloween II a worldwide total of $39,318,589.
Harris has continued to develop her scream queen identity with growing genre credits. She starred alongside Lance Henriksen, Bill Moseley, AFI's Davey Havok, and Battlestar Galactica's Nicki Clyne in the illustrated film series Godkiller. Beginning with 2010's Hatchet II, Harris has taken over the leading role of Marybeth in the Hatchet series, after Tamara Feldman declined to reprise her character. Further such credits include Jim Mickle's second feature film, the vampire/post-apocalyptic epic Stake Land, Cyrus: Mind of a Serial Killer, ChromeSkull, Shiver, Havenhurst, See No Evil 2 and Michael Biehn's The Victim, in addition to providing the voice and basis for an animated Barbara in Night of the Living Dead: Darkest Dawn, director Zebediah de Soto's prequel/re-telling of George A. Romero's 1968 original. She is set to star in William Forsythe's directorial debut, the vampire film New Blood. Harris' own directorial debut is the horror comedy Among Friends, in which she also makes an appearance. The film, which was picked up for distribution by Lions Gate Entertainment, was released on August 27, 2013.
During the 2010s, Harris has had guest appearances in the television shows Psych (as a murder suspect), Bones (as a murder victim), as herself in Holliston and Naked Vegas, and also returned to voice Debbie Thornberry for a saucy Robot Chicken parody of The Wild Thornberrys.
Harris has often been named "horror's reigning scream queen", by the New York Daily News and various other outlets, and was called "the Natalie Portman of Horror" by director Sylvia Soska. She has provided the cover feature for such publications as Girls and Corpses, Gorezone magazine, Invasion magazine and Scream Sirens as well as a subject for the photo-book The Bloody Best Project, a collection of artistic pictures showcasing the celebrities of the horror film industry. Harris was also featured in Five Finger Death Punch's first music video, "The Bleeding" of 2007. In 2011, Harris won the Best Actress Award at the Shockfest Film Festival for her starring role in the short Nice Guys Finish Last. The 2012 Burbank International Film Festival gave Harris its Best Actress Award for her portrayal of literary heroine Wendy Alden in Shiver.
In 2013, Harris became engaged to David Gross. The couple married in a private ceremony in Holualoa, Hawaii on January 4, 2014 and she gave birth to son Carter Davis Gross on February 21, 2017.In an interview in September 2013, Harris said that she would be taking a break from acting to focus on directing and to have a family.
Harris was stalked in 1995 by an obsessed fan, Christopher Small, who wrote letters threatening to kill her. Small was later arrested after bringing a shotgun and a teddy bear to her home. On January 29, 2007, Harris appeared on an episode of The Dr. Phil Show, sharing her experience with other equally affected people. The stalker was obsessed with her character of Molly Tilden from the television series Roseanne. In October 2009, Harris was granted a restraining order against Small, who began sending her messages on Twitter.