De Aza's two-run blast in the second inning and solo shot in the sixth made him the first White Sox player to homer twice on Opening Day since Jim Thome in 2008 at Cleveland.
Jose Abreu and Adam Dunn each drove in a run for the White Sox, who featured its first Opening Day lineup in 16 years that did not include first baseman Paul Konerko. Abreu, who signed a six-year, $68 million deal in the offseason, also doubled in his major league debut.
Chris Sale (1-0) recorded eight strikeouts and surrendered three runs on five hits in 7 1/3 innings of work. The left-hander finished fifth in the AL Cy Young Award voting last season. Matt Lindstrom picked up the save after allowing one hit and fanning a batter in a scoreless ninth.
Kurt Suzuki went 2-for-4 with three RBI for Minnesota, which dropped its sixth straight road opener. Chris Colabello and Aaron Hicks also supplied two hits apiece.
Ricky Nolasco (0-1) was reached for five runs on 10 hits with two walks and four strikeouts. He made his third Opening Day start after signing a four-year contract with the Twins in December.