2006–2012: Critical success
Set in Sorsogon, the Adolfo Alix-directed independent drama Donsol (2006) featured Aquino and Sid Lucero. The film tells the story of a woman suffering from breast cancer who returns to her hometown and finds companionship with a local whale shark spotter (played by Lucero). Aquino was drawn to her character's subdued and restrained personality, explaining, "It was a role I really wanted to play since it didn't call for a lot of bravura in acting. It was a quiet role which appealed to me". In preparation, she spent time with cancer support groups; and to get into her character's physical and mental space during filming, wore a chest binder and cut her hair short. Philip Cu-Unjieng of The Philippine Star found Aquino to be a "luminous screen presence", while Butch Francisco thought her portrayal was palpable and convincing. She won a Best Actress award at the 2006 Cinemalaya Independent Film Festival. Donsol received critical acclaim and accolades from several international film festival critics' organizations. It was submitted for consideration at the 80th Academy Awards for Best Foreign Language Film.
Aquino next starred alongside Cherry Pie Picache and Juliana Palermo in Brillante Mendoza's drama Summer Heat (2006), about a dysfunctional family with a controlling patriarch (played by Johnny Delgado). She received a Gawad Urian nomination for Best Actress. Her other film appearances in 2006 include Nasaan si Francis?, Ina, Anak, Pamilya, and Ang Pamana: The Inheritance. With Us Girls, Aquino returned as a television presenter for the lifestyle magazine show, which ran for six years. In 2007, Aquino portrayed a woman sending anonymous letters to Christopher de Leon's character in Eddie Romero's final directorial effort, Faces of Love (2007), which premiered at the 2007 Cinemalaya Independent Film Festival. Her next film part was as the television show producer in the supernatural horror Siquijor: Mystic Island, which reunited her with Mendoza. It is about a television crew who visits the island of Siquijor to film a documentary about local myths. That year, she also appeared in several television projects, including an episode of the anthology series Maalaala Mo Kaya, a role in the ensemble drama series Maging Sino Ka Man: Ang Pagbabalik, and as a presenter of the travel and food show Tablescape: Life On A Plate.
In 2008, Aquino starred in the short film God Only Knows directed by Mark Reyes. It was screened at the Asian American International Film Festival and Tribeca International Film Festival in New York City. She also featured in the supernatural fantasy series Lobo as a werewolf's mortal wife. Her next film release came in the Johnson & Johnson-produced family drama Botelya (2008), playing a single mother abandoned by an adulterous spouse. The following year, Aquino had a supporting role in All About Eve (2009), a remake of the eponymous South Korean show, starring Iza Calzado and Sunshine Dizon. The Ravelo Komiks Universe series Darna saw her portray the white stone keeper and original titular superhero, which was subsequently played by Marian Rivera.
To avoid being typecast in roles of martyred wives, Aquino accepted the offer to star as Vera Cruz, a prominent fashion designer and main antagonist, in the revenge drama series Magkaribal (2010). Unlike her previous assignments, the role allowed her to display an intimidating and hysterical personality. Aquino described her interpretation of Cruz as someone "always upset with everyone, always screaming at the top of her lungs", drawing inspiration from Agot Isidro's character in the television series Tayong Dalawa (2009). "They've designed the villainess ... in such a way that they will be sympathetic also, that they will be as real as possible", she said. She found herself challenged by the role and said that working on the project was a "daunting task", though she admitted that her personal experience working in the fashion industry drew her to the part. Her performance received generally positive reviews, with Ricky Lo of The Philippine Star finding Aquino to have "reaffirmed her thespian chops": "Watching Vera Cruz is like riding a roller-coaster of powerful emotions. One minute you hate her, wanting to crush her into pieces ... and the next you sympathize with her". She received a Star Award for Best Actress in a Drama Series nomination, and was also nominated in the Best Supporting Actress category at the Asian Television Awards for the role.
After a brief appearance in the family drama series Minsan Lang Kita Iibigin (2011), Aquino starred in the series remake Maria la del Barrio. As with Magkaribal, her role in the adaptation of the Mexican soap opera of the same name was the main villain. A journalist from The Philippine Star thought the show was compelling and found her portrayal noteworthy. In 2012, Aquino featured in R. D. Alba's dramatic thriller Biktima, portraying a journalist who has post-traumatic stress disorder after being abducted. She then played the lead role of a woman who is forced to care for her two sons after a car accident in the psychological horror Amorosa, directed by Topel Lee. Aquino, who has two children of her own, was drawn to the idea of playing a selfless mother and believed certain aspects of her character's life mirrored her own. The film only received a limited theatrical release. That same year, she co-starred with Isabelle Huppert in Mendoza's psychological thriller Captive. It is a partly fictionalized account of the year-long abduction of civilians by members of the Abu Sayyaf militant groups that began in a private island resort in Palawan. The film was presented at the 2012 Berlin International Film Festival.
