O'Brien, 25, connected on solo blast in the fourth inning off Nashville starter Sean Nolin, and then tagged right-hander Taylor Thompson for a two-run shot in his next at-bat.
It was the seventh multi-homer game of his career.
The corner outfielder has 23 home runs this season -- marking his third straight season with at least 20 -- to go along with a .286 batting average, .877 OPS and 93 RBIs in 118 games for Reno.
With 89 home runs in 395 career games, O'Brien's raw power is among the best in the Minor Leagues. Unfortunately, the 6-foot-4, 235-pound right-handed hitter has long struggled to make consistent contact, evidenced by his 25.4 percent career strikeout rate, while his aggressive approach continues to limit his on-base potential.
The Diamondbacks will need to add O'Brien to its 40-man roster this offseason to protect him from the Rule 5 Draft.
Mike Rosenbaum is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.