Mixon moved to Los Angeles, California, in 2003. In 2005, she starred in the premiere of the interactive theater play American Standard at the Los Angeles Edgefest. Mixon has performed at Upright Cabaret. Her first role in a major motion picture was in the 2005 thrillerThe Quiet, playing the character Michelle Fell.
As of 2012, Mixon is a regular cast member on the CBS TV series Mike & Molly. HBO's baseball comedy Eastbound & Down, thought to have finished its run in 2012 after three critically acclaimed seasons, was later announced to be returning for a fourth season. In 2013, Mixon reprised her role of April Buchanon in the fourth season.