"It felt like the entire world just came off my shoulders," Luplow said of his feelings rounding the bases. "It was nice seeing the smiles in the dugout. They were so happy for me."
First base coach Sandy Alomar Jr., who is filling in as manager while Terry Francona deals with health issues, said he stuck with Luplow because many of his at-bats were good.
"Sometimes you just want that first one to be a blooper, but I'll take a homer," Alomar said.
Domingo Santana added a solo homer in the eighth.
Plesac (1-1) allowed five hits and struck out seven in lowering his ERA to 1.29 this year.
The Cleveland pitching staff has allowed four runs or fewer in all 16 games this season.
Yoan Moncada homered in the eighth for Chicago. He has reached in 19 straight games dating back to last Sept. 25.
A wild pitch and a passed ball each scored runs. Reyes followed with his homer. Two batters later, Luplow, who struck out against Anderson in the third, connected for 6-0 lead.
"It pumps me up to go out there and put another zero up," Plesac said of the big inning. "We all know the offense is going to come around."
RHP Zack Burdi, a White Sox first-round pick in the 2016 draft, tossed a scoreless sixth inning with two strikeouts in his major league debut. Burdi, a native of nearby Downers Grove, was recalled from Chicago's alternate site at Schaumburg on Saturday morning.
"Being from Chicago and making your debut for the White Sox is what 50 percent of Chicago dreams of," Burdi said. "For me, this was my dream and what I thought about when I was a kid. This is a huge day for a lot of people and I'm really excited it's finally here and everyone was able to experience it."
White Sox: LHP Aaron Bummer (biceps strain) was placed on the 10-day injured list before the game. Bummer had to exit in the seventh inning Friday night. The 26-year-old has been a primary setup guy for Chicago with a 1.23 ERA in seven games this season. No determination has been made as to how long Bummer will be sidelined.
Cleveland ace Shane Bieber (3-0, 0.83 ERA) looks to win his fourth straight start Sunday night in the finale of the three-game series. RHP Lucas Giolito (1-1, 5.17) pitches for the White Sox. Bieber leads the majors with 35 strikeouts. It's the third-most strikeouts through three games in major league history. Nolan Ryan holds the record with 37 in 1973.
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