Headey had her first experience of acting when she was a pupil at Shelley College; she was noticed at age 17, when performing in a school production at the Royal National Theatre, and was picked for a role in the 1992 film Waterland.

At the age of 17, Headey performed in a one-off show and afterwards a casting agent took a photo and asked her to audition. She eventually obtained a supporting role in the drama Waterland (1992), in which she had the opportunity to work with actors who had been in the business several years before her. She also had a small role in the critically acclaimed 1993 drama film The Remains of the Day, which received eight Academy Awards nominations. Her career would continue to grow in England throughout the decade, and see larger parts in bigger motion pictures. In 1997, she appeared in the drama series Kavanagh QC, playing the role of Natasha Jackson.

Headey played Kitty Brydon, the childhood friend and romantic interest of Mowgli, in Disney’s The Jungle Book (1994). James Berardinelli praised the cast’s “solid performances” as part of a positive critical reception, and the film found moderate commercial success in theaters. She appeared opposite Vanessa Redgrave in the 1997 romantic drama Mrs Dalloway, portraying the closest friend of a housewife, who is now wife of a self-made millionnaire and mother of five. She was then cast in the drama Onegin (1999), a film based on the 19th-century Russian novel Eugene Onegin by Alexander Pushkin, in which she portrayed the fiancée of an aspiring poet and appeared with Ralph Fiennes and Liv Tyler. The film was critically and financially unsuccessful.

In 2000, Headey played a newly promoted lawyer with no apparent emotional attachments in the romantic comedy Aberdeen, receiving the Silver Iris Award for Best Actress at the 2001 Brussels European Film Festival, and also starred as a troubled college student in the psychological drama Gossip, with Kate Hudson. In 2001’s comedy The Parole Officer, Headey took on the role of a police officer, alongside Steve Coogan in his first film role. While the film was warmly received, ViewLondon remarked: “The only disappointment is Lena Headey, who, despite being fantastically sexy (she’s given both a nude scene and a ‘dressed as a prostitute’ scene), smirks her way through the entire film, even at the most inappropriate moments”.

In 2002, she appeared as a mousey Victorian lesbian artist with Gwyneth Paltrow and Aaron Eckhart in the mystery drama Possession, based on the 1990 novel of the same name by British author A. S. Byatt, and as the wife of a law-abiding art framer dying of leukemia in the thriller Ripley’s Game, adapted from the 1974 novel of the same name. In its review for the latter, Eye for Film noted: “Whilst this is very much a male-centered film, Lena Headey turns in a powerful performance as Jonathan’s wife, creating a sense of balance and normality against which other events are contrasted”. Headey appeared in the comedy The Actors (2003), opposite Dylan Moran and Michael Caine, portraying the love interest of a struggling actor. She is credited as voice actor for the character Callista in the video game Dishonored.

In 2005, Headey also starred with actress Piper Perabo in the films The Cave and Imagine Me & You. The horror film The Cave saw the actress play a member of a group of divers who become trapped in an underwater cave network. While critical response was negative, the film managed to turn a profit at the box office. In the romantic dramedy Imagine Me & You, she took on the role of a woman who falls in love at first sight with a newlywed bride who reciprocates her feelings; the newlywed struggles with whether to remain in a passionless marriage to a sweet husband, or pursue her electric connection to Heady’s character Luce. The film, which Commonsense Media called “charming”, “quirky” and “witty”, found a limited release in theaters, but Mick LaSalle from the San Francisco Chronicle stated that the actress “has a forthright, irresistible appeal and a face and especially a smile that suggest intelligence, integrity and lots of fun”.

Headey has been close friends with actress Piper Perabo since they starred together in the 2005 films The Cave and Imagine Me & You. She is also good friends with her Game of Thrones co-stars Pedro Pascal and Peter Dinklage, the latter of whom first suggested to producers on Game of Thrones that she be cast as Cersei Lannister.

Her most known film role came perhaps in 2007, when Headey played Queen Gorgo in Zack Snyder’s epic war film 300, based on the 1998 comic series of the same name by Frank Miller and Lynn Varley, a fictionalized retelling of the Battle of Thermopylae within the Persian Wars. Her character has a much larger role in the film than she does in the comic book, where she only appears in the beginning, and required her to film naked for one scene. “It’s always weird the thought of taking your clothes off in front of 20 people and then to have it projected in front of many more”, she said during an interview. “I think it was necessary because we only get that scene to establish their relationship. It is a very obvious moment but I think it does it in quite a beautiful way.” The film received mixed reviews, but was a box office success, grossing over US$450 million. In 2007, she also appeared as the stuffy Miss Dickinson in the sixth release of the St. Trinian’s film series.

She has appeared on the covers of TV Guide, G3, Sunday Mirror and Germany’s Filmstar. She ranked No. 64 on the Maxim magazine Hot 100 of 2007 list. She was listed at No. 4, No. 10 and No. 3 in AfterEllen’s list of the Hot 100 in 2007, 2008 and 2009, respectively.

Headey married musician Peter Loughran in May 2007; their son, Wylie Loughran, was born on 31 March 2010. She has spoken about suffering from postnatal depression following Wylie’s birth. Headey and Loughran separated in 2011, and she filed for divorce in the Los Angeles County Superior Court on 20 July 2012. The divorce was finalised on 26 December 2013. She was linked to Game of Thrones co-star Jerome Flynn. The relationship allegedly ended badly some time before March 2014, resulting in the two being kept apart on set. However, Flynn rebuffed the claims in 2019, saying the two had worked in a scene together, while adding “And the last time I saw Lena we were speaking, so I wouldn’t believe everything you read, and like I said, [the media] can get pretty desperate for stories.”

Headey starred as Fembot in Austin Powers, as well as Sarah Connor in Fox’s Terminator: The Sarah Connor Chronicles, a television spin-off of James Cameron’s popular Terminator franchise. The show ran for 31 episodes in two seasons, from January 2008 to April 2009. Variety praised “Headey’s gritty performance as Sarah —managing to be smart, resourceful and tough, yet melancholy and vulnerable as well”. For her performance, she was nominated twice for the Saturn Award for Best Actress on Television. In 2008, she starred alongside Matthias Schweighöfer and Joseph Fiennes in The Red Baron, a biographical film of the legendary World War I fighter pilot Manfred von Richthofen, appeared in Ridley Scott-produced sci-fi drama Tell-Tale, a film based on the short story by Edgar Allan Poe, and played a radiologist in the horror film The Broken, which premiered at the Sundance Film Festival. While the three aforementioned films went largely unnoticed by audiences, some critics praised Headey’s performance in The Broken, including Kim Koynar, of Cinematical, who wrote that Headey “largely carries the film, and does so quite ably”.

In 2009, Headey played an ill-fated character in the slasher film Laid to Rest, which received a DVD release, had a part in a short film titled The Devil’s Wedding, and also provided her voice for an episode of the Cartoon Network series The Super Hero Squad Show, playing Black Widow and Mystique. She briefly appeared in the independent comedy Pete Smalls Is Dead (2010).

Beginning in April 2011, Headey portrayed queen regent Cersei Lannister on the HBO series Game of Thrones, based on George R. R. Martin’s A Song of Ice and Fire series of novels. She was cast in the role after her friend and eventual co-star, Peter Dinklage, suggested her casting to producers. Her performance as the ruthless queen has received critical acclaim, earning a Scream Award nomination for Best Fantasy Actress for the role in 2011 and Primetime Emmy Award nominations for Outstanding Supporting Actress in a Drama Series in 2014, 2015, 2016, 2018 and 2019.

After guest-starring in the White Collar episode “Taking Account” in 2011, Headey took on the role of the leader of a drug dealing gang and the primary villain in the 3D sci-fi action film Dredd (2012), alongside Karl Urban and Olivia Thirlby. Her performance was inspired by punk-rock singer Patti Smith, and on the character, Headey asserted: “I think of [Ma-Ma] like an old great white shark who is just waiting for someone bigger and stronger to show up and kill her […] she’s ready for it. In fact, she can’t wait for it to happen […] She’s an addict, so she’s dead in that way, but that last knock just hasn’t come”. Despite a positive critical response, the film flopped at the box office, seeing greater success following its home release; it has since been recognised as a cult film.

Headey was vegetarian; however, in a 2011 interview she stated she now eats meat again, albeit rarely.

Following the success of 300 (2007), Headey reprised her role as Queen Gorgo in 300: Rise of an Empire, which was released in 2014. Like the first film, Rise of an Empire received mixed reviews, but was a major commercial success, grossing over US$337 million worldwide. In 2014, she also starred in the fantasy adventure film The Adventurer: The Curse of the Midas Box and the biographical film Low Down, which detailed the life of jazz pianist Joe Albany. In 2015, she played the wife of a federal prosecutor running for office who cannot stop himself from sleeping with high-class escorts in the political thriller Zipper, opposite Patrick Wilson.

On 10 July 2015, Headey gave birth to her second child, a daughter named Teddy, with director Dan Cadan (her childhood friend, who also worked with Headey on his short film The Devil’s Wedding). They had separated by June 2019.

Headey supports the LGBT rights organisation NOH8, and in April 2015 appeared on a T-shirt designed by them and sold through Represent.com to raise funds for the cause. She has been involved with humanitarian organization the International Rescue Committee (IRC), advocating for migrants languishing in Greece during the European migrant crisis, saying that in the face of rising populism, and the “lost humanity in leadership”, people should continue to “fight for the good”. In 2018, Headey did a voice-over for an advertisement by the charity Alzheimer’s Research UK, which launched ahead of World Alzheimer’s Day (21 September).

In the historical action comedy Pride and Prejudice and Zombies, Headey appeared as Lady Catherine de Bourgh, with her former Game of Thrones, Century and The Contractor co-star Charles Dance. Andrew Barker, of Variety, found her to be “excessively diverting” in what he considered a “tolerable, but not handsome enough” film. In 2017, Headey appeared as a “predictably hard-boiled boss” in the crime thriller Thumper, which premiered at the Tribeca Film Festival, and provided the voiceover for Mercedes A-Class television advertisement and Morgana in Trollhunters. She recently signed a first look deal with Platform One Media.