Sharapova, No. 1 in the world and the Wimbledon runner-up last year, won the first five games en route to a 6-2, 6-3 decision over Anastasia Rodionova.
Sharapova had 14 unforced errors -- four double faults -- in winning about two-thirds of the points as she coasted after the big early lead.
Williams, a five-time Wimbledon champion, fell to Elena Vesnina 6-1, 6-3 in a match between unseeded players. Williams managed just two break-point chances -- winning one -- while Vesnina finished off five of her eight opportunities.
It was Williams' first first-round loss at Wimbledon since her first appearance in the tournament in 1997. Her play has been sharply curtailed since she was diagnosed with Sjogren's syndrome, an autoimmune disease.
Kim Clijsters upset 18th-seeded Jelena Jankovic 6-2, 6-4 on the strength of five breaks. Clijsters, who said this will be her last Wimbledon tournament, had just 12 unforced errors and took more than half of the points off Jankovic's serve.
No. 3-seeded Agnieszka Radwanska stopped Magdalena Rybarikova 6-3, 6-3 behind six breaks and fifth-seeded Samantha Stosur defeated Carla Suarez Navarro 6-1, 6-3 in 62 minutes while eighth-seeded Angelique Kerber rolled by Lucie Hradecka 6-4, 6-1.
Also, 11th-seeded Li Na beat Ksenia Pervak 6-3, 6-1 with a dominant second set and 15th-seeded Sabine Lisicki stopped Petra Martic 6-4, 6-2.
But Camila Giorgi beat 16th-seeded Flavia Pennetta 6-4, 6-3 by losing her serve just once; Jamie Lee Hampton edged 28th-seeded Daniela Hantuchova 6-4, 7-6 (7-1); and Stephanie Foretz Gacon ousted 29th-seeded Monica Niculescu 6-4, 3-6, 6-4
Also advancing Monday were Tsvetana Pironkova, Sorana Cirstea, Bojana Jovanovski, Sloane Stephens, Andrea Hlavackova, Timea Babos, Hsieh Su-Wei, Ayumi Morita, Arantxa Rus, Anna Tatishvili, Silvia Soler-Espinosa, Ekaterina Makarova, Mathilde Johansson, Lourdes Dominguez Lino and British player Heather Watson.
Celebrity Couples of 2014 [PHOTOS]