Morgan was born in Seattle, Washington to Sandy Thomas and Richard Dean Morgan. He attended Ben Franklin Elementary School, Rose Hill Junior High, and Lake Washington High School in Kirkland, Washington, where he played football and captained the basketball team. He went on to play basketball at Skagit Valley College before being sidelined by injury.
Starting with Uncaged (1991), Morgan has appeared in over 25 feature films. However, the bulk of his work has been in television. He was the star of the 1996–1997 television series The Burning Zone; his character, Dr. Edward Marcase, appeared in 10 out of 19 episodes that season.
In 2005 and 2006, Morgan simultaneously appeared in three television series: in the CW series Supernatural as John Winchester, in a recurring role on ABC's Grey's Anatomy as heart transplant patient Denny Duquette, and as Judah Botwin in two episodes of the Showtime series Weeds. He has also guest-starred in a number of television series, including ER; JAG; Walker, Texas Ranger; Angel; CSI: Crime Scene Investigation; Sliders; The O.C.; and Monk. In 2007, Morgan was cast in a proposed project by Grey's Anatomy creator Shonda Rhimes. The series, tentatively titled "Correspondents", was to have started production in summer 2007. ABC instead picked up a spin-off of Grey's Anatomy, called Private Practice, that was also created by Rhimes. As a result, "Correspondents" was shelved.
In 2007, Morgan starred in the film The Accidental Husband, which finished filming in March 2007 and was released on DVD in 2009.
Morgan starred in the thriller The Resident and the drama film Days of Wrath in 2008.
In 2009, Morgan portrayed The Comedian, a cigar-chomping antihero, in Watchmen, based on Alan Moore's graphic novel. The same year, Morgan appeared in Taking Woodstock, and played Clay in a comic book movie adaptation of The Losers.
Morgan appeared in the Texas crime thriller Texas Killing Fields as a homicide detective in 2011. The following year, Morgan starred in the television drama series Magic City, which centered on mob life in 1950s Miami. The same year, Morgan appeared in the horror thriller The Possession, and the war film Red Dawn. It was announced in January 2014, that Morgan had been cast in the lead role in Jonás Cuarón's Desierto.
In 2014, Morgan played Charlie Peters, the owner of the Cake House, in the season finale of Shameless. He's only appears for a couple of episodes before Fiona Gallagher, who (like Peters) is a drug addict works at Patsy Pies with a different boss.
In November 2014, Morgan was cast as Joe DiMaggio opposite Kelli Garner as Marilyn Monroe in The Secret Life of Marilyn Monroe, a Lifetime four-hour miniseries based on J. Randy Taraborrelli's book of the same name.
In 2015, Morgan portrayed Deaf Smith in Texas Rising, a five-part mini-series which aired on the History Channel. Also in 2015, Morgan became a regular cast member for season 2 of the CBS sci-fi drama Extant. He also appeared in an uncredited role in Batman v Superman: Dawn of Justice, as Bruce Wayne's father, Thomas Wayne.
In 2015, Morgan took on the role of freelance investigator Jason Crouse, opposite Julianna Margulies, in the popular CBS TV series The Good Wife, until that series' conclusion in spring 2016.
In 2016, Morgan began to portray the character Negan on the AMC TV series The Walking Dead. He made his first appearance in the sixth-season finale on April 3, 2016 and served as the primary antagonist of the seventh and eighth seasons.
On May 28, 2017, Morgan drove the 2017 Chevrolet Corvette Grand Sport Pace Car to lead the starting field of the 101st Indianapolis 500.
In September of 2017, Morgan appeared in a commercial for the online game Evony.
On May 30, 1992, Morgan was married to actress Anya Longwell in Las Vegas. In 2007, he was briefly engaged to his former Weeds costar Mary-Louise Parker; their engagement ended in April 2008.
In 2009, Morgan began a relationship with actress Hilarie Burton. The couple's son Augustus "Gus" was born in March 2010. In July, 2015, Morgan said that despite media reports to the contrary, he and Burton were not yet married but that they intended to wed when he could get enough time off from work.
Morgan and Burton made their home in the town of Rhinebeck in Dutchess County, New York on a working farm with cows, chickens and alpacas. Since 2014, they have been co-owners (along with Morgan's friend, actor Paul Rudd) of Samuel's Sweet Shop, a Rhinebeck candy store they saved from being closed after the previous owner, a friend of theirs, died suddenly.
In a June 2015 appearance on Jimmy Kimmel Live!, he was asked how many children he had and replied "I have one", referring to his son with Hilarie Burton. In September 2017, it was announced that the couple is expecting their second child.