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Hayek's portrayal of painter Frida Kahlo in the biopic Frida (2002), which she also produced, made her the first Mexican actress nominated for the Academy Award for Best Actress. In subsequent years, Hayek focused more on producing while starring in the action-centred pictures Once Upon a Time in Mexico(2003), After the Sunset (2004) and Bandidas(2006). She achieved further commercial success with the comedies Grown Ups (2010), Grown Ups 2 (2013) and The Hitman's Bodyguard (2017). She lent her voice to the animated Puss in Boots(2011), Sausage Party (2016) and Puss in Boots: The Last Wish (2022). She also earned critical acclaim for her performances in the dramas Tale of Tales (2015), Beatriz at Dinner (2017) and House of Gucci (2021). She played Ajak in the Marvel Cinematic Universe film Eternals (2021), which emerged as her highest-grossing live-action film.

Hayek's directing, producing and acting work on television has earned her four Emmy Awards nominations. She won the Daytime Emmy Award for Outstanding Directing in a Children's Special for The Maldonado Miracle (2004). She received two Primetime Emmy Award nominations, one for Outstanding Guest Actress in a Comedy Series and the other for Outstanding Comedy Series, for her work on the ABC television comedy-drama Ugly Betty (2006–2010). She also produced and played Minerva Mirabal in the Showtime film In the Time of the Butterflies (2001) and guest-starred on the NBC comedy series 30 Rock (2009–2013).

As a public figure, Hayek has been cited as one of Hollywood's most powerful and influential Latina actresses and one of the world's most beautiful women by various media outlets. Time magazine named her one of the 100 most influential people in the world in 2023. In 2021, she was honoured with a  Hollywood Walk of Fame star. She is married to business magnate François-Henri Pinault, with whom she has a daughter.