In 2004, Curtis moved from GMA Network to ABS-CBN, stating the move “majorly life changing.” She then acted alongside Dina Bonnevie and Kris Aquino in Hiram, which aired until 2005. Aside from Hiram, Curtis also joined ASAP as a host and as a performer.

Curtis’ big break came in 2005 when she won the title role in the television series Kampanerang Kuba. This marked her first collaboration with director Wenn V. Deramas. Curtis admitted that Deramas was eyeing another actress for the role, but she auditioned anyway. In this project, she got the chance to work with veteran actresses Eula Valdez and Jean Garcia. Curtis then hosted the reality show Qpids with Luis Manzano, and a segment in The Buzz called Wannabuzz.

In 2006, Curtis, along with Luis Manzano, hosted Star Circle Summer Kid Quest. That same year, she starred in All About Love, a three-in-one love flick where she co-starred with John Lloyd Cruz, Bea Alonzo, Luis Manzano, Angelica Panganiban and Jason Abalos. She then filmed Wag Kang Lilingon with Kristine Hermosa. She portrayed Celine Magsaysay in the drama series Maging Sino Ka Man where she received raved reviews for her performance. and received a nomination for Best Drama Actress at the PMPC Star Awards for TV.

In 2008, Curtis starred in When Love Begins, a romantic drama film where she was paired with Aga Muhlach. In July 2008, Curtis was announced to play the lead role in Baler, alongside Jericho Rosales. The film was an official entry to 2008 Metro Manila Film Festival. Her performance in the film was critically lauded, leading to a Metro Manila Film Festival Award for Best Actress. This marked Curtis’ first acting award. She also received a FAMAS Award for Best Actress nomination, a PMPC Star Award for Movies for Movie Actress of the Year nomination, a Gawad PASADO Award for Pinakapasadong Aktress nomination, and a Luna Award for Best Actress nomination. Also in 2008, Curtis topbilled the television series Dyosa. She played four different characters in the said series. Because of her role in this series, she was dubbed as the “Dyosa” of Philippine Showbiz.

She became one of the main hosts of the morning variety show, Showtime in 2009 which included Vhong Navarro, Kim Atienza and Vice Ganda. Also in 2009, she starred in the television series, The Wedding, with Zanjoe Marudo and Derek Ramsay.

In 2010, she starred in the film Babe, I Love You. The movie marked her first big-screen team-up with Sam Milby. Her second film for 2010 was In Your Eyes alongside Claudine Barretto and Richard Gutierrez. Her role in this film earned her a Luna Award for Best Supporting Actress and a Movie Actress of the Year nomination at the PMPC Star Awards for Movies.

In 2011, she starred in the Philippine adaptation of the Korean series, Green Rose. where she starred again with Jericho Rosales. She also topbilled the film Who’s That Girl?, which served as her reunion movie with Luis Manzano. Although a confessed non-singer, Curtis launched her debut album, Annebisyosa, under Viva Records, on 25 September 2011. She asked for her bosses to release her album, as it is one of her dreams. She described her album as “super fun” and “not serious.” She also stated that people should listen at their own risk. In October 2011, the album reached the gold status, as it sold 10,000 copies. Curtis cried while receiving the gold record award. The album reached the Platinum status in December 2011. On 28 September 2011, her film No Other Woman, which also starred Derek Ramsay and Cristine Reyes, was released. It grossed Php 100 million in five days. The film became the highest-grossing film in the Philippines, until it was beaten by The Unkabogable Praybeyt Benjamin. Her performance in the film lead her and co-star Cristine Reyes to be recognised as the Box Office Queens at the Guillermo Mendoza Memorial Foundation’s Box-Office Entertainment Awards. She also won as the Pinakapasadong Aktres at the Gawad Pasado Awards and received a FAMAS Award for Best Actress. At PMPC Star Awards for Movies, she was nominated as Movie Actress of the Year.

On 28 January 2012, Curtis staged her first solo concert entitled Annebisyosa: No Other Concert World Tour at the Smart Araneta Coliseum. The concert was also in celebration of her 15th year in show business. Vhong Navarro, Luis Manzano, Vice Ganda, Rico Blanco, Ira Cruz, Sam Milby, Derek Ramsay, Cristine Reyes Afterwards, several provincial concerts were held. She also performed internationally in cities such as Hong Kong and California. Also in 2012, Curtis’ show Showtime replaced Happy Yipee Yehey! in the noontime slot. She also starred in the movie, A Secret Affair, which earned her third FAMAS Award for Best Actress nomination.

In 2013, Curtis, along with Kris Aquino and Robin Padilla, led the drama series, Kailangan Ko’y Ikaw.

Curtis’ projects in 2014 included her playing the title role in ABS-CBN’s adaptation of Mars Ravelo’s Dyesebel, comedy film The Gifted and her second studio album The Forbidden. She had her second solo concert titled ‘The Forbidden Concert Annekapal’ in May at the Smart Araneta Coliseum.

In 2015, the ‘Kuyakoy’ moves of Curtis started to become viral online then eventually called as the ‘Kuyakoy Queen’. In 2016, she became the host of I Love OPM, alongside Erik Nicolas, a singing competition which involves foreign people. She also guested in FPJ’s Ang Probinsyano with Christopher De Leon

In March 2015, Curtis became a celebrity advocate for UNICEF Philippines, having been a supporter of the organization since 2009. As an advocate, she visited parts of Leyte that were devastated by Typhoon Haiyan (Yolanda) in 2013 to meet with children and families affected by the typhoon and observe recovery operations. In October 2015, Curtis launched a marathon called the “Heroes for Children Run” to benefit UNICEF’s “1,000 Days of Life” campaign. In February 2016, Curtis announced that she had written a children’s book entitled Anita, The Duckling Diva in collaboration with UNICEF Philippines.

In December 2016, Curtis became engaged to her longtime boyfriend, restaurateur and food blogger Erwan Heussaff; they tied the knot on 12 November 2017 in Queenstown, New Zealand. Curtis gave birth to the couple’s child, Dahlia Amélie on 2 March 2020. Some netizens say that the name “Dahlia” was taken from the name of Anne’s character in her 1997 movie Magic Kingdom, directed by Peque Gallaga for Viva Films.

In September 2017, Anne Curtis launched her makeup line in the Philippines, BLK cosmetics.

In 2018, she starred with Dingdong Dantes in the film Sid & Aya: Not a Love Story. In the same year, she top-billed Buy Bust in which she received critical acclaim from critics and the film became a commercial success. In December 2018, her horror-thriller film Aurora served as an official entry to the 2018 Manila Film Festival and marked Curtis’ third and last film of 2018. In 2019, she starred alongside with Marco Gumabao in the film Just a Stranger which became a box-office success and received critical acclaim for both Curtis and Gumabao. In December 2019, she starred alongside her It’s Showtime co-host, Vice Ganda in their film The Mall, The Merrier which served as an official entry to the 2019 Metro Manila Film Festival. It became a box-office hit but received mixed to average reviews from critics. In early 2020, Curtis announced her hiatus to focus on her pregnancy and personal life.

In preparation for her role in the 2018 film BuyBust, Curtis became a practitioner of Pekiti-Tirsia Kali a school of Filipino Martial Arts founded in 1897 by the Tortal family.