In 1991 Hayek moved to Los Angeles to pursue a film career, and to study acting under Stella Adler, having limited fluency in English, and dyslexia. After taking a small part in the 1993 film Mi vida loca, she was noticed by director Robert Rodriguez and his co-producer and then-wife, Elizabeth Avellan, soon gave Hayek a starring role opposite Antonio Banderas in 1995’s Desperado. She followed her role in Desperado with a brief role as a vampire queen in From Dusk till Dawn, in which she performed an erotic table-top snake dance.

At the age of 23, Hayek landed the title role in Teresa (1989), a successful Mexican telenovela that made her a star in Mexico. In 1994, Hayek starred in the film El Callejón de los Milagros (Miracle Alley), which has won more awards than any other movie in the history of Mexican cinema. For her performance, Hayek was nominated for an Ariel Award.

Hayek had a starring role opposite Matthew Perry in the 1997 romantic comedy Fools Rush In. In 1999, she co-starred in Will Smith’s Wild Wild West. She also played a supporting role in Kevin Smith’s Dogma film as Serendipity. In 2000, Hayek had an uncredited acting part opposite Benicio del Toro in Traffic. In 2003, she reprised her role from Desperado by appearing in Once Upon a Time in Mexico, the final film of the Mariachi Trilogy.

Hayek has been a spokeswoman for Avon cosmetics since February 2004. She was a spokeswoman for Revlon in 1998. In 2001, she modeled for Chopard and was featured in 2006 Campari ads, photographed by Mario Testino. On April 3, 2009, she helped introduce La Doña, a watch by Cartier inspired by fellow Mexican actress María Félix.

Around 2000, Hayek founded film production company Ventanarosa, through which she produces film and television projects. Her first feature as a producer was 1999’s El Coronel No Tiene Quien Le Escriba, Mexico’s official selection for submission for Best Foreign Film at the Oscars.

Hayek was an executive producer of Ugly Betty, a television series that aired around the world from 2006 to 2010. Hayek adapted the series for American television with Ben Silverman, who acquired the rights and scripts from the Colombian telenovela Yo Soy Betty La Fea in 2001. Originally intended as a half-hour sitcom for NBC in 2004, the project would later be picked up by ABC for the 2006–2007 season with Silvio Horta also producing. Hayek guest-starred on Ugly Betty as Sofia Reyes, a magazine editor. She also had a cameo playing an actress in the telenovela within the show. The show won a Golden Globe Award for Best Comedy Series in 2007. Hayek’s performance as Sofia resulted in a nomination for Outstanding Guest Actress in a Comedy Series at the 59th Primetime Emmy Awards.

Frida, co-produced by Hayek, was released in 2002. Starring Hayek as Frida Kahlo, and Alfred Molina as her unfaithful husband, Diego Rivera, the film was directed by Julie Taymor and featured an entourage of stars in supporting and minor roles (Valeria Golino, Ashley Judd, Edward Norton, Geoffrey Rush) and cameos (Antonio Banderas). She earned a Best Actress Academy Award nomination for her performance.

In 2003, Hayek produced and directed The Maldonado Miracle, a Showtime movie based on the book of the same name, winning her a Daytime Emmy Award for Outstanding Directing in a Children/Youth/Family Special. In December 2005, she directed a music video for Prince, titled “Te Amo Corazon” (“I love you, sweetheart”) that featured Mía Maestro.

Hayek’s charitable work includes increasing awareness on violence against women and discrimination against immigrants. On July 19, 2005, Hayek testified before the U.S. Senate Committee on the Judiciary supporting reauthorizing the Violence Against Women Act. In February 2006, she donated $25,000 to a Coatzacoalcos, Mexico, shelter for battered women and another $50,000 to Monterrey based anti-domestic violence groups. Hayek is a board member of V-Day, the charity founded by playwright Eve Ensler. Nonetheless, Hayek has stated that she is not a feminist. She later revised her stance on this, stating: “I am a feminist because a lot of amazing women have made me who I am today. (…) But – it should not be just because I am a woman”.

In April 2007, Hayek finalized negotiations with MGM to become the CEO of her own Latin-themed film production company, Ventanarosa. The following month, she signed a two-year deal with ABC for Ventanarosa to develop projects for the network.

In July 2007, The Hollywood Reporter ranked Hayek fourth in their inaugural Latino Power 50, a list of the most powerful members of the Hollywood Latino community. That same month, a poll found Hayek to be the “sexiest celebrity” out of a field of 3,000 celebrities (male and female); according to the poll, “65 percent of the U.S. population would use the term ‘sexy’ to describe her”. In 2008, she was awarded the Women in Film Lucy Award in recognition of her excellence and innovation in her creative works that have enhanced the perception of women through the medium of television. In December of that year, Entertainment Weekly ranked Hayek number 17 in their list of the “25 Smartest People in TV.”

Hayek is a naturalized United States citizen. She studied at Ramtha’s School of Enlightenment and is a practitioner of yoga. Hayek, who was raised Catholic, stated in a 2007 interview that she was no longer devout, and did not believe in the Church, in part because she disagreed with practices such as its campaign against condoms in Africa, where AIDS and overpopulation was rampant, though she clarified that she still believed in Jesus Christ and God.

On March 9, 2007, Hayek confirmed her engagement to French billionaire and Kering CEO François-Henri Pinault as well as her pregnancy. She gave birth to her daughter Valentina Paloma Pinault on September 21, 2007 at Cedars-Sinai Medical Center in Los Angeles, California. They were married on Valentine’s Day 2009 in Paris. On April 25, 2009, they held a second ceremony in Venice.

In 2008, Hayek co-founded Juice Generation’s juice delivery program Cooler Cleanse. In 2017, she and Juice Generation founder Eric Helms launched the beauty subscription delivery service Blend It Yourself, based on Hayek’s personal beauty elixirs. It supplies subscribers with the prepared organic frozen smoothie and acai bowl ingredients, some of which can also be applied as face masks. She also wrote the foreword to Helms’ 2014 book The Juice Generation: 100 Recipes for Fresh Juices and Superfood Smoothies.

In 2010, Hayek’s humanitarian work earned her a nomination for the VH1 Do Something Awards. In 2013, Hayek launched with Beyoncé and Frida Giannini a Gucci campaign, “Chime for Change”, that aims to spread female empowerment.

Hayek was raised in a wealthy, devout Catholic family, and at age 12 was sent to the Academy of the Sacred Heart in Grand Coteau, Louisiana. In school, she was diagnosed with dyslexia. She attended university at the Universidad Iberoamericana where she studied International Relations. In a 2011 interview with V magazine, Hayek mentioned that she was once an illegal immigrant in the United States, although it was not for a long period of time.

In 2011, Hayek launched her own line of cosmetics, skincare, and haircare products called Nuance by Salma Hayek, to be sold at CVS stores in North America. Hayek was also featured in a series of Spanish language commercials for Lincoln cars.

Hayek played the wife of Adam Sandler’s character in the buddy comedy Grown Ups, which also co-starred Chris Rock and Kevin James. At his insistence, Hayek co-starred with Antonio Banderas in the Shrek spin-off film Puss in Boots as the voice of the character Kitty Softpaws, who serves as Puss in Boots’s female counterpart and love interest. In 2012, Hayek directed Jada Pinkett Smith in the music video “Nada Se Compara.” She reprised her role in Grown Ups 2, which was released in July 2013.

Salma Hayek Jiménez was born in Coatzacoalcos, Veracruz, Mexico. Her father, Sami Hayek Domínguez, is a Lebanese Mexican, hailing from the city of Baabdat, Lebanon, a city Salma and her father visited in 2015 to promote her movie Kahlil Gibran’s The Prophet. He owns an industrial-equipment firm and is an oil company executive in Mexico, who once ran for mayor of Coatzacoalcos. Her mother, Diana Jiménez Medina, is an opera singer and talent scout, and is a Mexican of Spanish descent. In an interview in 2015 with Un Nuevo Día while visiting Madrid, Hayek described herself as fifty-percent Lebanese and fifty-percent Spanish, stating that her grandmother/maternal great-grandparents were from Spain. Her younger brother, Sami (born 1972), is a furniture designer.

For International Women’s Day 2014 Hayek was one of the artist signatories of Amnesty International’s letter, to then British Prime Minister David Cameron, campaigning for women’s rights in Afghanistan. Following her visit to Lebanon in 2015, Hayek criticized the discrimination against women there.

On December 13, 2017, Hayek published an op-ed in The New York Times stating that she had been harassed and abused by film producer Harvey Weinstein during the production of Frida.

At the 2019 San Diego Comic-Con it was announced that she will star as Ajak in the Marvel Cinematic Universe film The Eternals, directed by Chloé Zhao and scheduled to be theatrically released in the United States on February 12, 2021.

In 2019, the Pinault family pledged US$113 million to support the reconstruction efforts of the burned Notre Dame Cathedral in Paris, France.

In 2020, Hayek raised awareness for the disappearance of Vanessa Guillen through her Instagram.