The third-seeded former world No. 1 Sharapova blitzed Colombian qualifier Mariana Duque-Marino 6-1, 6-2, while the fourth-seeded Kvitova held off American Coco Vandeweghe 6-4, 2-6, 6-3 on the red clay at the Magic Box.
The Wimbledon champ Kvitova was the Madrid titlist back in 2011.
In other action involving seeds, rising Frenchwoman Caroline Garcia took out No. 14 Czech Karolina Pliskova 6-2, 4-6, 6-1 and Russian Anastasia Pavlyuchenkova upended No. 15 Italian Sara Errani 3-6, 7-6 (9-7), 6-4. Pliskova was fresh off her clay-court title in Prague.
Also on Day 4, Czech Barbora Strycova topped American Varvara Lepchenko 6-4, 6-2 and former world No. 1 and two-time Madrid runner-up Victoria Azarenka erased Croat Ajla Tomljanovic 6-3, 6-3.
Azarenka is rewarded with a third-round match against the current world No. 1 Williams, who captured back-to-back Madrid titles in 2012 and 2013 and has yet to lose this year, going 22-0. The powerful American has won her last 25 matches overall, dating back to November.
Williams is 14-3 lifetime against the Belarusian star Azarenka, including a victory in the 2012 final here in Madrid.