Leigh was born in Charlotte, North Carolina. She is the daughter of Yvonne Norton and Robert Potts. Leigh was raised in Virginia Beach, Virginia, where her parents ran a weight-loss business. However, when Leigh was eight, the business went bankrupt and at the age of twelve, following the break-up of her parents' marriage, Leigh moved with her mother and brother, future Power Rangers In Space actor Christopher Khayman Lee, to Miami where her mother remarried her first husband. Following her parents' divorce, Leigh was estranged from her father for many years, but they have since reconciled.
While in eighth grade, she started modelling. She soon began acting by appearing in local television commercials and a syndicated teen news show called Hall Pass. In 1999, Leigh and her mother relocated to Los Angeles in order for Leigh to develop a career in acting. At age 16, Leigh took and passed the California High School Proficiency Exam.
At age 16, Leigh met her future husband, 20-year-old Nathan West, when they both attended auditions for the pilot of an unsuccessful WB series titled Saving Graces. They began a relationship, and Leigh left home to move in with West. Leigh described them as being "broken", both having had troubled family lives and difficult upbringings. This led to abuse of drugs such as cocaine, which quickly escalated into addiction. The catalysts for change eventually came in 2001, when Leigh, in the throes of addiction and barely eating, was told by the director of Not Another Teen Movie that she looked unhealthily thin. Around that time, she and West also attended a Christian church service, at the invitation of a friend, which helped them break free of their addiction. Clean and sober in 2002, they were wed in Alaska surrounded by their closest family and friends.
Leigh started acting at an early age and debuted in the film world at age 15 in 1997's Kickboxing Academy. She started hosting in local TV shows and modeling; in 2001, Leigh nabbed the lead role in the box-office success Not Another Teen Movie as Janey Briggs. She also appeared in Marilyn Manson's music video "Tainted Love", a song which appeared in the film. She was ranked #65 on the Maxim Hot 100 Women of 2002. In 2002, Leigh was cast in two short-lived TV series: Girls Club, in which she played lawyer Sarah Mickle, and That '80s Show, in which she played punk rocker June Tuesday. She then became a series regular on the ABC legal drama The Practice, but was let go at the end of the season due to budget cuts. Following that, she joined the cast of Reunion in September, 2005.
In ABC's Grey's Anatomy, Leigh first appeared as a woman in Joe's bar who was noticed by Derek Shepherd while in the third-season finale, it was revealed that she was Lexie Grey. She was made an official series regular for season four, and remained so until the eighth-season finale.
Chyler Leigh also makes music with her husband Nathan West (East of Eli), under the name "WestLeigh". They have performed covers and originals songs. In 2015, for their thirteenth anniversary they wrote "Love Lit The Sky". On Saint Valentine's Day 2017 they released a single "Nowhere" and then she take part in tours.
On June 18, 2017 was released a single "Spirit of Samba" of Laurent Voulzy feat. Chyler Leigh, Nina Miranda, Luisa Maita and Eloisia; in France has reached its maximum with the 99th position of the Syndicat National de l'Édition Phonographique (SNEP).
In October, 2015, she began starring, in a lead role, in the CBS/CW show Supergirl as Alexandra "Alex" Danvers, who is the sister of Supergirl.
On July 20, 2002, Leigh married fellow actor Nathan West in Alaska. The couple worked together in 2000 on the television series 7th Heaven, playing Mary Camden's (Jessica Biel) troubled friends Frankie and Johnnie. Leigh and West have three children – a son and two daughters: Noah Wilde (born December 2003), Taelyn Leigh (born September 2006), and Anniston Kae (born May 7, 2009).
Leigh has said that she and her husband have a pact in which the person who guesses the baby's sex correctly gets to choose the name. When pregnant with Noah, she guessed she was having a boy so she chose the first name and Nathan gave him his middle name. For Taelyn, Nathan correctly guessed it was a girl, so he named her. Their third child, also a girl, was guessed correctly by West; he chose the name Anniston Kae.
Leigh is a Christian and credits her faith and a "really awesome church" with giving her and her husband "a reason to live". She also supports The Thirst Project, a non-profit organization in America which aims to bring safe drinking water to communities around the world.
Chyler Leigh and her family live in Los Angeles.