At 19 years, after graduating from Valley High School in Albuquerque, NM, Kelly returned to Los Angeles. While on a test shoot for a modeling agency, she was approached by a former Playboy Playmate interested in managing her, and who placed Minka Kelly as a receptionist at a surgeon's office who would provide Minka Kelly breast augmentation in exchange for hours worked. She ultimately decided against the procedure, leading to her being fired. However, the exposure to the medical field prompted her to attend school for a year to become a surgeon's assistant; afterward, she worked as a scrub tech. She spent four years in that vocation while also auditioning as an actress before landing the new NBC television drama Friday Night Lights, based on the high school football movie of that name. In the interim, she had small roles in movies and shows, including the film State's Evidence, and a recurring guest role on the TV sitcom What I Like About You.
In preparation for her role as cheerleader Lyla Garrity on Friday Night Lights, she trained with the Pflugerville High School cheerleading squad. Kelly received praise for her acting on the series, with The New York Times calling her performance "heartbreaking."
Minka Kelly shot a cameo for The Kingdom, alongside Jamie Foxx. Peter Berg, the creator and pilot director of Friday Night Lights, directed the film. Minka Kelly was the lead actor on The CW's 2009 pilot Body Politic, which did not go to series. Minka Kelly was a member of the ensemble quartet that starred in the CBS comedy pilot Mad Love, playing Kate, a Midwestern girl who falls in love with Henry at the top of the Empire State Building, but was replaced by Sarah Chalke.
Kelly appeared with Alyson Hannigan, Jaime King, Emily Deschanel, and Katharine McPhee in a video slumber party featured on FunnyorDie.com to promote regular breast cancer screenings for the organization Stand Up 2 Cancer.
In 2010, ABC announced that Minka Kelly would join the cast of the upcoming remake of the television series Charlie's Angels. That same year, Minka Kelly also was named "Sexiest Woman Alive" in the annual Esquire magazine feature. She accepted a role in the Off Broadway play Love, Loss, and What I Wore for an April 27 through May 29, 2011 run with Conchata Ferrell, AnnaLynne McCord, Anne Meara, and B. Smith.