Mattek-Sands started her year representing the U.S. in the 2012 Hopman Cup with Mardy Fish. She came up short in her singles matches against Wimbledon champion, Petra Kvitová of the Czech Republic and Denmark's world No. 1, Caroline Wozniacki, but beat Bulgaria's Tsvetana Pironkova in the third tie. After an early exit from the Hopman Cup, she played singles at the Moorilla Hobart International, where she was a finalist, and doubles with partner Gajdošová. In singles, she lost in the second round to Sorana Cîrstea, and in doubles, she reached the semifinals, before having to retire due to a neck injury.