It took all of two minutes and 45 seconds for Notre Dame to dig too deep of a hole against the Sooners.
The Irish lost by 14 points, 35-21, after spotting Oklahoma that same margin in the opening moments.
"You just can't turn the football over the way we did," said head coach Brian Kelly of Tommy Rees' back-to-back interceptions. The first was returned for a touchdown and the second led to a short TD drive for Oklahoma. "If we take care of the football, we might be in overtime right now."
"As a quarterback your job is to erase negative plays when you know things aren't perfect," said Rees, who finished with three interceptions in the game. "I got to be smarter with that and know when plays aren't run the way we're supposed to."
"We feel the offense lost this game for us," senior wide receiver and captain TJ Jones said. "I'm not speaking for the offense as a whole but in my opinion I feel we gave them 14 points with those two interceptions. And our defense played their butts off."
Despite the early deficit, the Irish did have success running the ball with a season-high 220 yards.
They were led by George Atkinson's career-high 148 yards. The performance was a blend of speed and physicality from the junior.
"We told him if he wanted to be the starter, that he can't get tackled by his ankles," said Kelly. "He's 220 pounds and I thought he ran the ball today like I expect George Atkinson to run the ball."
"It wasn't good enough to win the game," a subdued Atkinson said after the game. "Doesn't matter if I got one carry for one yard. As long as we win, it doesn't matter."
Saturday's defeat was the first for Notre Dame in the Stadium since October 2011 against USC. It ended a streak of ten consecutive wins at home.
The Irish face Arizona State in Texas next week for the annual Shamrock Series game.