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Garner gained recognition for her leading performance as CIA officer Sydney Bristow in the ABC spy-action thriller television series Alias (2001–2006). For her work on the series, she won the Golden Globe for Best Actress – Television Series Drama and the Screen Actors Guild Award for Best Actress in a Television Drama, in addition to four consecutive nominations for the Primetime Emmy Award for Outstanding Lead Actress in a Drama Series. She received additional praise for her performance in the romantic comedy 13 Going on 30 (2004), and went on to portray Elektra in the superhero films Daredevil (2003) and Elektra (2005). She continued to achieve commercial success with performances in the comedy-drama Juno (2007), and the romantic comedies Ghosts of Girlfriends Past (2009) and Valentine's Day (2010).

Garner had starring film roles in the fantasy-comedy The Invention of Lying (2009), the fantasy drama The Odd Life of Timothy Green (2012), and the biographic drama Dallas Buyers Club (2013), the latter of which earned her a nomination for the Screen Actors Guild Award for Outstanding Performance by a Cast in a Motion Picture. She went on to star in the family comedy Alexander and the Terrible, Horrible, No Good, Very Bad Day (2014), the drama Miracles from Heaven (2016), the romantic comedy-drama Love, Simon (2018), the HBO comedy series Camping (2018), the action thriller Peppermint (2018) and action-comedy The Adam Project (2022). Garner has also produced and starred in the comedy Butter (2011) and the family adventure Yes Day (2021).

Garner works as an activist for early childhood education and is a board member of Save the Children USA. She is the co-founder and chief brand officer of the organic baby food company Once Upon a Farm. She is also an advocate for anti-paparazzi campaigns among children of celebrities.