Ortiz appeared in several television shows including NYPD Blue, Everybody Loves Raymond, Commander In Chief, ER, and The New Adventures of Old Christine. She had her first series regular role in short-lived NBC comedy series Kristin (2001). She later starred in another short-lived sitcom, called A.U.S.A. in 2003, and later had recurring roles in the FX drama Over There, and ABC series Boston Legal.

In 2006, Ortiz was cast as Hilda Suarez, the lead character’s sister, in the ABC comedy-drama series Ugly Betty. Originally, Ortiz had auditioned for the Betty Suarez role, saying in 2008, “I was super plain. I just put on some glasses and kept my hair kind of flat and layered on the clothing”, describing what she wore when auditioning for the role of Betty. “I just wanted them to remember me, so that I could be involved in the future”.

In addition to her role on Ugly Betty, Ortiz was active in films, which include starring roles in Tortilla Heaven and Labor Pains. She also had a voice role in Batman: Gotham Knight, and starred in the made-for-television movie Little Girl Lost: The Delimar Vera Story in 2008. Ortiz also had a guest-starring role on Army Wives during its second season, playing a waitress named Sandi. She also appeared in the 2010 music video for Enrique Iglesias and Juan Luis Guerra’s “Cuando me enamoro”.

After Ugly Betty ended in 2010, Ortiz was cast as lead character in the ABC drama pilot True Blue about San Francisco homicide detectives reunited to solve the murder of one of their own. The pilot was not picked up to series. The following year she appeared in the comedy film Big Mommas: Like Father, Like Son, and starred in another pilot, called Outnumbered for Fox, her second pilot not picked up to series. She later had a recurring role on the HBO comedy series Hung. Ortiz also starred in the independent films Sleeping with the Fishes, and Such Good People.

Ortiz married musician Noah Lebenzon in June 07, 2007 in Rincón, Puerto Rico. Their daughter Paloma was born June 25, 2009. Their second child, son Rafael, was born on September 24, 2011.

In 2012, Ortiz was cast as a lead character on the ABC comedy-drama pilot Devious Maids. While ABC chose not to pick it up to series, Lifetime picked up the pilot with a thirteen-episode order. The series premiered June 23, 2013, on Lifetime with positive reviews from critics. In the show, she plays the lead role of Marisol Duarte (the alias of Professor Marisol Suarez). Also in 2013, Ortiz was special guest star in the ABC primetime soap opera, Revenge, as Bizzy Preston. In 2014, Ortiz guest-starred in episodes of two ABC shows: How to Get Away with Murder and Black-ish.

In 2014 Ortiz was cast in the gay-drama film Love is All You Need? (2016), based on the 2011 short film with the same name. She did voice over work in the 2018 film Ralph Breaks the Internet.

Devious Maids was canceled after four seasons, in 2016. The following year, Ortiz starred in her third unsold pilot, a comedy called Charlie Foxtrot. Since 2019, Ortiz appears in the main cast of the comedy drama Whiskey Cavalier, playing FBI profiler Susan Sampson.

In 2020, Ortiz starred in the acclamed Hulu series Love, Victor as Isabel Salazar, mother of the title character Victor Salazar. Her role is acclamed by critics.