Santana's first inning blast helped spoil the return of White Sox pitcher Carlos Rodon (0-1) from Tommy John surgery. The left-hander gave up five runs in 3 2/3 innings in his first appearance since May 1, 2019.
''They took some good pitches, fouled off some good pitches - they made me work,'' said Rodon, who struck out four. ''So tip the cap to that, obviously. When I got ahead two strikes, you could tell anytime they saw spin they were laying off.''
Cleveland won the opener 4-3 behind a career-high nine strikeouts by Aaron Civale and home runs from Francisco Lindor and Bradley Zimmer. The Indians did not trail in the twinbill and have not experienced a lead change in their first five games.
Mercado drove in Franmil Reyes and Domingo Santana in the fourth, extending Cleveland's lead to 5-1. James McCann hit a solo homer for Chicago in the second, and Jose Abreu added another in the sixth off right-hander Adam Plutko (1-0).
Abreu, who went 3 for 4, doubled in the eighth and scored on Nicky Delmonico's single that pulled the White Sox within 5-3. Zack Collins followed with a drive to the wall in center, but Mercado made a tremendous leaping catch to end the inning.
''I honestly did not think I'd be able to catch it when I went up,'' Mercado said. ''It was a big play for sure. They're both nice, but I would rather come up with a big play than a big hit.''
Rookie Cam Hill earned his first save with a perfect ninth. Plutko struck out four over six innings in his season debut.
''I poured quite a few Bud Lights over Cam to celebrate his first career save,'' Plutko said. ''He has been really, really good in the minor leagues, so I hope he soaks it all in.''
Carlos Santana and Jose Ramirez had two hits apiece for the Indians, who have won three in a row. Santana reached base in all four plate appearances in the opener and played all 18 innings at first base.
''Carlos loves to play and he doesn't want to take an inning off, ever,'' Cleveland manager Terry Francona said. ''There are so many reasons why we're fond of him.''
White Sox manager Rick Renteria, who had been isolated in a downtown hotel after experiencing a cough and a stuffy nose Monday, rejoined the team after testing negative for COVID-19.
The 58-year-old said he was diagnosed with a chest cold. Renteria did not miss a game because the series opener was rained out.
White Sox RHP Ian Hamilton worked a scoreless sixth in his first game in the majors since Sept. 25, 2018. He was struck by a foul ball last June while sitting in the dugout with Triple-A Charlotte, suffering multiple facial fractures and catastrophic dental damage. ''As long as my teeth don't fall out, they'll be good for now,'' Hamilton quipped.
HE'S GOT IT
White Sox rookie CF Luis Robert raced to straight-away right and stepped in front of RF Leury Garcia to catch a routine fly ball in the fifth inning of the nightcap. Garcia seemed stunned that Robert came all the way over to catch the can of corn, throwing up his hands and jokingly signaling for Robert to get back to his spot.
White Sox: OF Eloy Jimenez (head) took batting practice and ran the bases but was held out of both games. The 23-year-old slugger was hurt Sunday when he crashed into the left field wall against Minnesota.
Indians: C Roberto Perez (right shoulder soreness) was unavailable for the nightcap after going 0 for 4 in the opener. C Beau Taylor was selected from Cleveland's alternate training site between games.
White Sox: RHP Lucas Giolito (0-1, 17.18 ERA) allowed seven runs in 3 2/3 innings on opening day against Minnesota. He has thrown 14 2/3 consecutive scoreless frames against the Indians.
Indians: RHP Shane Bieber (1-0, 0.00 ERA) starts the three-game series finale Wednesday. The 2019 All-Star Game MVP struck out 14 over six scoreless innings against Kansas City on opening day.
More AP MLB: https://apnews.com/MLB and https://twitter.com/AP-Sports
Copyright 2020 STATS LLC and Associated Press. Any commercial use or distribution without the express written consent of STATS LLC and Associated Press is strictly prohibited.