Mattek-Sands had seven breaks in the 11 games that Radwanska served en route to a 7-5, 6-2 second-round victory.
Mattek-Sands had won three qualifying matches and a first-rounder for a shot at Radwanska, who is No. 5 in the world rankings. Radwanska had a 5-3 lead in the first set but Mattek-Sands caught a second wind and reeled off seven consecutive games to take the first set and go up 3-0 in the second.
It was the fifth consecutive loss for Radwanska, who was beaten by world No. 1 Serena Williams in the semifinals in Beijing and then dropped all three of her round-robin matches at the WTA Championship's last year. Tuesday marked her first match of 2014.
Lucie Safarova also posted an upset, taking out sixth-seeded Caroline Wozniacki 6-4, 7-6 (9-7) in about 2 hours.
Second-seeded Petra Kvitova was very sharp in 6-1, 6-0 romp past Christina McHale. Kvitova won 71 percent of the points on serve and 59 percent when receiving in the hour-long match.
Also Tuesday in second-round action, Madison Keys beat Ajla Tomljanovic 6-0, 3-6, 7-6 (7-3), Carla Suarez Navarro topped Ekaterina Makarova 7-6 (7-4), 6-3; and Tsvetana Pironkova defeated Varvara Lepchenko 6-3, 6-2.