Kaepernick threw two touchdown passes to Vernon Davis, one right after the first of three interceptions by Romo, and the 49ers opened the season with a 28-17 win over the sloppy Cowboys on Sunday.
The 49ers (1-0) also got a 35-yard fumble return on the second play of the game when Chris Culliver picked up a loose ball stripped from DeMarco Murray. They led 21-3 after the first quarter despite running just four offensive plays.
Coming off a spotty preseason for his offense, Kaepernick was efficient, going 16 of 23 for 201 yards without an interception.
Romo was playing his first meaningful game for the Cowboys (0-1) since back surgery in December.
San Francisco's secondary made up for a front seven missing the suspended Aldon Smith and the injured NaVorro Bowman. Safety Eric Reid returned the first interception 48 yards to the Dallas 2, setting up Kaepernick's second scoring toss to Davis.
The Dallas defense was supposed to be the problem after the league's worst unit from a year ago released franchise sacks leader DeMarcus Ware in a salary cap move and lost middle linebacker Sean Lee to a season-ending knee injury in the offseason.
Romo looked like a quarterback who was limited in the offseason and training camp, not a good start for a team trying to avoid tying a franchise record with a fifth straight year of missing the playoffs.
He didn't see Reid on a throw to Dez Bryant, then didn't see wide-open receiver Dwayne Harris for an easy touchdown. Instead he forced a pass to Jason Witten that was intercepted by Patrick Willis in the end zone.
The interceptions kept coming even after starting San Francisco cornerbacks Tramaine Brock (toe) and Culliver (concussion) had been knocked out of the game. Backup Perrish Cox had his second career pick when Romo threw deep to Dez Bryant in double coverage.
It didn't take Kaepernick long to put that rough preseason behind him, leading the 49ers 80 yards in just three plays on their first possession. He stepped out of an ankle tackle by Jeremy Mincey and threw 29 yards on the run to Davis, who juggled the ball as the crossed the goal line before holding on for a 14-3 lead.
The 49ers also had an efficient drive in their 2-minute offense to finish the first half, with Kaepernick throwing for 39 yards leading to Carlos Hyde's 4-yard scoring run for a 28-3 halftime lead.
When Romo wasn't throwing interceptions, the Dallas offense was getting false-start penalties and using timeouts to avoid delay-of-game penalties.
Part of the problem was the noise from large swaths of red-clad 49ers fans seeing their team for the first time in the regular season in the $1.2 billion home of the Cowboys.
Murray bounced back from the fumble on his first carry of the season to get 71 yards in the first quarter and 118 with a touchdown for the game.
But he didn't get the ball on second-and-1 from the San Francisco 2 with a chance to tie the score early. Instead, Romo was sacked and Dallas settled for a field goal.
Instead it was the Dallas offense that caused most of the trouble for the Cowboys as 49ers coach Jim Harbaugh, the only coach since the 1970 merger to lead a team to a conference title game in each of his first three seasons, improved to 4-0 in season openers.