That second inning featured a pair of home runs, the first from designated player Katie Norris to put OU up 4-0 at the time.
Pitcher Keilani Ricketts, who exited the circle after throwing a perfect three innings, smashed a grand slam to make it 8-0.
Norris and Ricketts each had two more RBI in the inning, while second baseman Georgia Casey recorded an RBI single and first baseman Lauren Chamberlain, who blasted a first inning two-run shot, ripped a two-RBI single up the middle to put OU up a healthy 15-0 through two frames.
"It's exciting, especially being the first game of the postseason, just to open up like that," said Ricketts, who admitted she hadn't really been a part of an inning like that before. "You could just tell that we were ready for it."
But they weren't done there.
The Sooners added three more in the third, boosted by RBI singles from Casey and third baseman Javen Henson.
Pinch hitter Allee Allen plated Henson on a fielder's choice to put OU up 18-0.
"This was a team that was very anxious to play," said OU head coach Patty Gasso. "They just came out of the blocks and unloaded from the start."
Lehigh did manage to get on the scoreboard in the fourth on catcher Liz Lucas' three-run bomb to left.
OU added its final run in the bottom half when left fielder Brittany Williams homered to right.
The Sooners' four homers broke the previous Big 12 single season record of 88 set by Texas back in 2010, as they now have 89.
Their run total also served as the second most ever scored by an OU team in the postseason as they tied club regional records for RBIs (19) and home runs.
"It was really one of the most dominating performances I've seen from an OU team in every way, shape and form," Gasso said. "I just thought the way they looked defensively and the way we were throwing the ball around. The way Keilani looked on the mound, very dominating. Offensively there was not one really routine easy play that I felt or saw throughout the game. So, I think what we're saying is we mean business and we want this as much as anybody out there."
Chamberlain and Norris each had four RBIs, while Ricketts finished with six while going 2-for-3 with seven total bases (a homer and triple) in that monster second inning.
OU faces Tulsa in the winner's bracket game at 1 p.m. Saturday.