She has been involved in advocacy on a number of poker-related issues including advocating for the legality of online gambling and for players' rights to control their own image.

She enrolled at Columbia University, joining the first co-ed class in its 230-year history, and pursued a double major in English and psychology.

[1][12][13] After graduating from Columbia, she pursued a Ph.D. in psychology at the University of Pennsylvania, focusing on cognitive linguistics and writing her dissertation on a hypothesis of how children learn their first language called "syntactic bootstrapping".

[17] More than 30 years after leaving graduate school, she returned to the University of Pennsylvania in the fall of 2022, earning her Ph.D. in cognitive psychology in June 2023.

Following a successful year playing in Montana, her brother prompted her to enter tournaments at the 1994 World Series of Poker (WSOP) in Las Vegas.

[1] Later in 2004, she placed first in the inaugural WSOP Tournament of Champions, beating her brother and nine former world championship winners and winning $2 million.

[28] In 2010, Duke won the NBC National Heads-Up Poker Championship; she outlasted a field of 64 players, including eliminating previous winner Huck Seed, and defeating Erik Seidel in the final match.

[34] No evidence was presented against Duke and there was no investigation of such with regard to any involvement or benefiting from any fraudulent crimes pertaining to the company.

On two occasions, Duke has testified in Congress on behalf of the Poker Players Alliance regarding the legality of Internet gambling.

[36] In 2013, audio recordings released by Travis Makar proved that Duke knew about the so-called God Mode but did not use it to swindle players as it was on a time delay.

Filing records show Federated Sports + Gaming owed creditors more than $8 million, while Duke earned at least $299,000 in salary.

[48] During 2011, Duke and Eric Faulkner, the CIO of Federated Sports + Gaming, created the Global poker index (GPI).

Duke, actor Don Cheadle, and a mutual friend, Norman Epstein, co-founded the non-profit Ante Up for Africa in 2007 to raise money with poker tournaments for charities benefiting African countries.

[44][58] The first tournament in July 2007 was held at the start of the World Series of Poker[27] and raised more than $700,000, which was donated to the ENOUGH Project and the International Rescue Committee.

[44][59] In 2008, 2009 and 2010, money raised in the organization's tournaments was again donated to the ENOUGH Project, and also to Not On Our Watch,[60] Refugees International,[61] Water.org, and the Eastern Congo Initiative.

[65] Duke has played in and hosted charitable poker tournaments for organizations including Life Rolls On, the Cystic Fibrosis Foundation, and Boston Children's Hospital,[55] for which she helped to raise $500,000 in 2007[27] and $425,000 in 2012.

[68] From 2007, Duke served as a member of the board of directors for the Decision Education Foundation, a non-profit organization based in Palo Alto, California which provides training for teachers and mentors to produce curricula focused on decision-making skills for their students.

[70] In 2014, Annie Duke founded How I Decide,[71] a nonprofit to help young people develop the essential life skills of critical thinking and decision making.

[73][74] In the mid-2000s, Duke was a producer and consultant for All In, a pilot television show for NBC based on her life, in which she was portrayed by Janeane Garofalo; the series was not picked up by the network.