The tall Russian, who won the grasscourt Grand Slam in 2004 as a 17-year-old, slipped over a couple of times during the match and received lengthy treatment after a particularly nasty fall in the seventh game of the second set.
Even before the tumble, which was very similar to the one that ended up forcing second seed Victoria Azarenka to withdraw with a knee injury, Sharapova was outplayed by the world number 131 who sealed victory on her fifth match point when her opponent netted a forehand.
Sharapova's exit came hours after the withdrawal of second seed Azarenka, who called for Wimbledon officials to investigate why the courts were so slippery after several players suffered falls, and their departure opens up the bottom half of the draw.
After claiming victory the 20-year-old De Brito clearly had some sympathy for her opponent.
"There's lot of grass that's been cut and not been swept up so there's a lot of dead grass so it's not been easy," she told the BBC. "It's a tough court to play on."
Former world number one Sharapova never looked happy on Court Two against a tenacious opponent, who shares the same noisy style of play as the four-times Grand Slam champion and hails from the same Florida tennis academy.
While being treated in the second set after the tumble that left her clutching her hip, Sharapova appeared to complain to the umpire that the surface was "dangerous".
She went off court to continue treatment and resumed after a near 10-minute stoppage but the Russian, who seemed to struggle with her serve in an all-round error-ridden performance, could not avoid one of her worst results at the All England Club.
With ninth seed Caroline Wozniacki and 12th seed Ana Ivanovic both losing the lower half of the women's draw is now seriously short of big names.
Round 2 results:
Flavia Pennetta (Italy) beat 2-Victoria Azarenka (Belarus)WO
Michelle Larcher de Brito (Portugal) beat 3-Maria Sharapova (Russia) 6-3 6-4
8-Petra Kvitova (Czech Republic) beat Yaroslava Shvedova (Kazakhstan)WO
Petra Cetkovska (Czech Republic) beat 9-Caroline Wozniacki (Denmark) 6-2 6-2
Eugenie Bouchard (Canada) beat 12-Ana Ivanovic (Serbia) 6-3 6-3
15-Marion Bartoli (France) beat Christina Mchale (U.S.) 7-5 6-4
Vesna Dolonc (Serbia) beat 16-Jelena Jankovic (Serbia) 7-5 6-2
17-Sloane Stephens (U.S.) beat Andrea Petkovic (Germany) 7-6(2) 2-6 8-6
19-Carla Suarez Navarro (Spain) beat Mirjana Lucic-Baroni (Croatia) 1-6 6-3 6-3
20-Kirsten Flipkens (Belgium) beat Bojana Jovanovski (Serbia) 6-4 6-4
Camila Giorgi (Italy) beat 22-Sorana Cirstea (Romania) 7-6(7) 7-6(6)
25-Ekaterina Makarova (Russia) beat Garbine Muguruza Blanco (Spain) 6-2 6-7(3) 6-4
Karin Knapp (Italy) beat 27-Lucie Safarova (Czech Republic) 4-6 6-4 6-4
29-Alize Cornet (France) beat Hsieh Su-Wei (Taiwan) 6-3 6-2
Eva Birnerova (Czech Republic) beat Lesia Tsurenko (Ukraine) 6-3 6-4
Monica Puig (Puerto Rico) beat Silvia Soler Espinosa (Spain) 6-2 5-7 6-4
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- Victoria Azarenka