The towering three-run shot upped his RBI total to 55, also best in baseball, and capped a tiebreaking six-run outburst in the eighth.
"Kind of weird. Going from the other side of the plate is totally different than coming around like I used to,'' Cruz said. "It was overall a good day."
Cruz was in the lineup after being hit in the left hand by Houston's Scott Feldman and left Sunday's game in the third inning. X-rays were negative.
Cruz said he came in to get treatment on Monday, an off day for the club, and was able to grip a bat.
The 33-year-old outfielder and designated hitter was the American League player of the week and is leading David Ortiz in the All-Star balloting at DH.
Cruz is back in Globe Life Park in Arlington for the first time since a must-win Game 163 last season, when the Rangers lost to the Tampa Bay Rays and missed the postseason for the first time since 2009.
"It's weird," Cruz said about returning in a different uniform. "I've been here for so long and now to be on the other side is different."
Cruz said he's talked to several Rangers players and had dinner with a few of them on Monday night. He hopes to get a good reception from fans.
"You always try to expect the best, so hopefully I hear some cheers," Cruz said.
Cruz missed 50 games last season after serving his suspension for using performance-enhancing drugs and still managed to hit 27 homers and drive in 76 runs in 109 games before the suspension.
Cruz was a key cog in the Rangers' World Series teams in 2010 and 2011 and was the ALCS MVP in 2011 with a record six home runs and 13 RBIs in Texas' six-game win over Detroit.
Cruz was a career .268 hitter in parts of eight seasons in Texas with 157 home runs and 489 RBIs.
The Rangers made a $14.3 million qualifying offer to Cruz over the offseason, but Cruz rejected it in hopes of securing a multiyear deal. That never materialized, something he admitted he was "surprised" about. But that situation allowed the Orioles to scoop him up for $8 million plus incentives, with the promise that he could play some outfield in addition to appearing in the DH spot.
Cruz looks fondly on his time in Texas and said he has no hard feelings.
"I cannot be more thankful for the Rangers," Cruz said. "They gave me a chance to be a major league player. The coaches, they teach me how to play baseball and how to be a professional."
The Associated Press contributed to this report.
Cruz Hits 21st Home Run In Return To Texas
After getting hit in the hand Sunday, Nelson Cruz didn't miss any time and hit a three-run homer in the Orioles' 8-3 victory over the Rangers.
Nelson Cruz To Start For Orioles
Alex Cora breaks down the return of Nelson Cruz to the Orioles' lineup.