Meester was born in Fort Worth, Texas, to Constance Lynn (née Haas) and Douglas Jay Meester. Her father is a real estate broker; her mother is a writer. She has two brothers: an older brother, Douglas Logan Meester (born 1983), and a younger brother, Alexander “Lex” Meester (born 1994). At the time of her birth, Meester’s parents were serving time in a federal prison for their involvement in a drug ring that smuggled marijuana from Jamaica to the United States. Constance was able to give birth to Leighton in a hospital and nurse her for three months in a halfway house, before returning to prison to complete her sentence. Her paternal grandparents cared for Meester during this period. She has maintained that her parents gave her a normal upbringing and, despite their criminal past, has stated, “It made me realize that you can’t judge anyone—especially your parents—for what they’ve done in their past, because people change.” She grew up in Marco Island, Florida, where she participated in productions at a local playhouse. Her parents separated in 1992.

Meester made her acting debut in 1999 as a murder victim’s friend, Alyssa Turner, on an episode of Law & Order. Following this, she made her film debut in Hangman’s Curse (2003), based on the bestselling book by Frank Peretti. She had a series regular role in Tarzan, which aired for only eight episodes. A recurring role in Entourage as Justine Chapin and Veronica Mars as Carrie Bishop followed in 2004 and 2005. Meester booked guest roles in the series Crossing Jordan, 8 Simple Rules, 7th Heaven and 24. She was cast as series regular in Surface as Savannah Barnett.

In 2006, Meester appeared in two films, Flourish and Inside. She also guest starred in an episode of Numbers and appeared in two episodes of House as Ali Johnson, a teenager who has a crush on Gregory House. She then had guest roles on CSI: Miami and Shark, and portrayed the female lead in the horror film Drive-Thru, for which she recorded the song “Inside the Black”. Meester was cast as identical twin sisters Kayla and Kelly Rhodes in the ABC crime-drama series Secrets of a Small Town, but the network decided not to forward the series.

In 2007, Meester was cast in The CW’s teen drama series Gossip Girl as Blair Waldorf, based on the book series of the same name by Cecily von Ziegesar. She first auditioned for the role of Serena van der Woodsen, but told the producers that she could better play Blair. However, it was important that Serena was blonde and Blair was brunette, so Meester dyed her hair brown for the role. Her performance was the most critically acclaimed of the show, with Blair being cited as the series’ breakout character. She also garnered media attention for her wardrobe on the show. The series ended after six seasons and 120 episodes. Meester later starred in the television film The Haunting of Sorority Row, and had a role in the ensemble comedy-drama film Remember the Daze. In 2008, she appeared in the horror-thriller film Killer Movie and reprised her role in Entourage singing with Tony Bennett in the episode.

Meester has participated in several charitable campaigns. In 2008, she was a spokesperson for Sunsilk’s “Life Can’t Wait” campaign, which aimed at motivating women to pursue their dreams. She also collaborated with Safe Horizon in 2009 to raise awareness about domestic violence. In 2015, Meester auctioned off fashion and accessories in a charity auction on eBay. The proceeds benefited Many Hopes, a charity organization that builds schools and homes for children in Kenya.

Meester has been included in magazine lists of the world’s most beautiful women. Meester was named one of People magazine’s “100 Most Beautiful” in 2008. She was ranked #48 on Maxim magazine’s “Hot 100 of 2008” list and #12 on “Hot 100 of 2009” list. FHM magazine’s ranked her #1 on their list of “Fall TV’s Hottest Stars” in 2008. Meester has been included on The Independent Critics’ list of “100 Most Beautiful Famous Faces”. She ranked #21 in 2008, #14 in 2009, #4 in 2010, #36 in 2011, and #76 in 2012.

Early in 2009, Meester partnered with Reebok to model their new Top Down sneakers. Apart from Gossip Girl, Meester worked with co-star Ed Westwick in a Nikon Coolpix series camera advertisement, and both were the faces of the Korean clothing line ASK Enquired. In April 2009, she released the song “Birthday” featuring duo Awesome New Republic. A version without her vocals was included on their Rational Geographic Vol. I album. Later that month, Meester signed a recording contract with Universal Republic. Meester provided vocals on Cobra Starship’s song “Good Girls Go Bad”, which peaked at number seven on the Billboard Hot 100. In July, “Body Control” surfaced on the internet. Meester’s first official single, “Somebody to Love”, featuring R&B singer Robin Thicke, was released for airplay on October 13, 2009, and became available for digital download on October 14, 2009. She recorded a cover of the song “Christmas (Baby Please Come Home)” for the compilation album A Very Special Christmas 7.

Her second single, “Your Love’s a Drug”, was digitally released on March 30, 2010, and she is also featured on Stephen Jerzak’s song “She Said”. Meester did a duet with DJ Clinton Sparks on “Front Cut”, which appeared on the internet in February 2011. Lil Wayne worked with her on an unreleased song titled “Make It Rain” and Jesse McCartney wrote another song. The album was produced by Polow Da Don, Harvey Mason Jr., and Spencer Nezey. Meester began working on it in March 2009 and the album was initially projected to be released in the fall of 2009, but was later delayed to early 2010. It was pushed back again to late 2010, and was ultimately shelved.

Meester had small roles in the comedies Date Night and Going the Distance. She then starred with Gwyneth Paltrow and Garrett Hedlund in the country music drama Country Strong. Wesley Morris of The Boston Globe described Meester as the best part of the film, writing, “She’s just doing Reese Witherspoon’s June Carter Cash in Walk the Line with dabs of Miley Cyrus and Kellie Pickler. But it’s not an impersonation; it’s a performance with its own comedy and sweetness.” Claudia Puig of USA Today was also positive, stating “Meester shows she can do more than play one of Gossip Girl’s privileged Manhattan socialites.” For the film, Meester recorded a cover of the song “Words I Couldn’t Say” by Rascal Flatts as well as “A Little Bit Stronger” by Sara Evans featured on the film’s soundtrack; a promotional single titled “Summer Girl”; and a duet with Garrett Hedlund titled “Give In To Me”. After wrapping, she received a guitar from Tim McGraw and decided to learn how to play it. In October 2010, Meester said she had been working with a band called Check in the Dark and had been writing for the last six months after being inspired by Country Strong. She revealed her influences, “I love Neil Young and Joni Mitchell, that style of music, and as far as songwriting I think that’s where my heart is.”

In 2010, Meester signed on to be the spokesperson for Herbal Essences hair products. In the same year, she took part in Bulgari’s humanitarian efforts for the Save the Children organization with Isabella Rossellini and Maribel Verdú. She next fronted a beauty campaign for Korean brand eSpoir. Vera Wang selected her to be the face of the fragrance Lovestruck in 2011, stating that Meester’s “beauty, talent and spirit will inspire all the young women that I hope will enjoy this passionate, new young fragrance.” The next year, Meester shot a campaign for the follow-up fragrance, Lovestruck Floral Rush. Italian fashion house Missoni named Meester the face of their spring/summer 2011 campaign.

In July 2011, Meester and her mother, Constance, filed lawsuits against each other over Meester’s financial support of her younger brother, Alexander, who has multiple health problems. Meester’s suit claimed that her mother used the money she sent for “cosmetic procedures”, such as botox and hair extensions. Her mother’s suit made a counterclaim alleging breach of contract and physical abuse. Constance claimed that a verbal contract was in place where Meester had promised US$10,000 a month, instead of the US$7,500 she received. Her mother also claimed that she was due a larger sum in return for “sacrificing her own happiness” when she moved Meester to Los Angeles as a child to pursue acting. In court, the judge dismissed this claim. Constance accused her daughter of calling social services and fabricating a claim that she was abusing Alexander; investigators interviewed Meester and found no merit in the complaint. In November 2011, Constance dropped the US$3 million claim for damages against her daughter. Meester said that she would be willing to pay for her brother’s medical expenses as well as his school tuition, but denied that she agreed to pay US$10,000 each month, which she stated was a “ridiculous” claim. Meester obtained a default judgment on December 7, 2011. In June 2012, Meester won the lawsuit, with the judge rejecting the claims in her mother’s counter-suit.

In April 2012, Meester announced via Twitter a five-city tour with Check in the Dark, which started on May 29 and ended on June 4, 2012. Reflecting on her past pop collaborations, she said she “loved” them, but that folk music was “a lot closer to [her] heart.” In May 2012, she endorsed the Philippine clothing brand Penshoppe’s campaign All Stars. In June, Meester said she and the band had recorded all the songs for an album that served as a demo.

She next starred in the comedy film That’s My Boy, alongside Adam Sandler, Andy Samberg, and Milo Ventimiglia, which was released in June 2012. The film received mainly negative reviews, was nominated for eight Golden Raspberry Awards, and was a box office failure, grossing less than $58 million, failing to recoup its production budget of $70 million. In August 2012, Meester, Wilmer Valderrama and Vanessa Curry appeared in house music group The Nomads’ music video for “Addicted to Love”. She was unavailable to reprise her role as Carrie Bishop in the film Veronica Mars due to scheduling issues, and was replaced by singer Andrea Estella of the band Twin Sister. In October 2013, Biotherm, a French luxury skincare company, announced Meester as its new global ambassador.

Meester has graced the cover of numerous international fashion magazines, including US’ Lucky, Flaunt, Shape, Nylon, Allure, Teen Vogue, Harper’s Bazaar and Rolling Stone; Indonesia’s Elle, Marie Claire, Cosmopolitan and CosmoGirl; UK’s Company and InStyle; Morocco’s L’Officiel; Australia’s Cleo; Mexico’s GQ and Seventeen; Russia’s Elle Girl and Joy and Italy’s Glamour. She has appeared in commercials and print ads throughout her career. She has appeared in print ads for Missoni, Reebok, Herbal Essences, Vera Wang and Jimmy Choo. In 2013, she worked as a global brand ambassador for skin care company Biotherm.

Meester resides in Los Angeles. In November 2013, she became engaged to actor Adam Brody, whom she met while filming The Oranges in March 2010. The couple was married in a private ceremony on February 15, 2014. Their first child, daughter Arlo Day Brody, was born on August 4, 2015. In April 2020, it was revealed that the couple were expecting their second child. In September 2020, Brody confirmed their second child, a son, was born.

In April 2014, her comedy film Life Partners premiered at the Tribeca Film Festival. It follows the friendship between a lesbian (Meester) and a straight woman (Gillian Jacobs) who begin a new relationship. Meester made her Broadway debut in the stage adaptation of John Steinbeck’s novel Of Mice and Men, starring opposite James Franco and Chris O’Dowd. The production filmed and broadcast in cinemas for one night through National Theatre Live, the first Broadway production to be selected by the program. She then appeared opposite Robert Downey, Jr., Robert Duvall, and Vera Farmiga in the David Dobkin-directed comedy-drama film The Judge, which premiered at the Toronto International Film Festival and released in October 2014. Meester next appeared in Like Sunday, Like Rain directed by Frank Whaley, playing the girlfriend of Green Day’s singer Billie Joe Armstrong, and By the Gun, alongside Ben Barnes. She won the Best Actress Award for Like Sunday, Like Rain at the 2014 Williamsburg Independent Film Festival. She was the face of French brand Naf Naf’s autumn/winter 2014 collection.

On September 9, 2014, it was announced her debut album, Heartstrings, would be released independently through her own label, Hotly Wanting, on October 28. With its style compared to ethereal singer-songwriters such as Tori Amos and Joni Mitchell, the nine-song LP was written by Meester and produced by Jeff Trott. The music video for the eponymous title track “Heartstrings” was released on October 29.

In 2015, Meester embarked on a tour to support the album, which began on January 6 in Los Angeles, California and ended on March 2 in San Francisco, California. Later that year, she appeared in advertisements for the Malaysian fashion brand Jimmy Choo. Meester was one of the 100 celebrity narrators featured in the documentary Unity, which had a limited theatrical release. In March 2016, she was cast in Fox’s comedy series Making History as Deborah Revere, a colonial woman from 1775 and the daughter of American artisan Paul Revere. The series was cancelled after one season of nine episodes. Meester had a guest role on The Last Man on Earth.

Meester has been volunteering with the non-profit organization Feeding America since 2017. During her first two years working with Feeding America, she has volunteered at Los Angeles’ Downtown Women’s Center and assisted with relief efforts in Puerto Rico after Hurricane Maria in 2017. Meester and Adam Brody also worked with children at Para Los Niños Charter School in Los Angeles, where they helped the organization serve lunches to children. In January 2019, she participated in Feeding America’s campaign with Subway and Shamrock Farms. For every child’s meal with milk purchased on January 11, 2019 at Subway, $1 will be donated to Feeding America to fight hunger and homelessness.

In January 2018, Meester joined the cast of Semper Fi, starring alongside Jai Courtney, Nat Wolff and Finn Wittrock, which was released in October 2019. Meester starred in ABC’s Single Parents alongside Taran Killam, which premiered in September 2018 and was cancelled after two seasons. In 2019, Meester was a guest star in an episode of The Orville titled “Lasting Impressions” as Laura Huggins.

In May 2019, Meester worked together with Feeding America and Los Angeles Food Bank to help families in need. “Together, we helped fill grocery baskets for families who lined up to receive important staples, like fruit, rice and cereal,” Meester wrote in an Instagram post.