Tolzien, who has been the Colts' No. 1 quarterback in Andrew Luck's absence since April, threw two interceptions that were returned for touchdowns, including one on the Colts' first offensive series. And he was nearly intercepted a third time, if not for receiver Donte Moncrief getting called for a face mask penalty while breaking up the pass near the Colts' sideline.
Tolzien, who entered the game 0-2-1 as a starter in his career, finished 9 of 18 passing for 128 yards with two interceptions and was sacked four times.
The Colts acquired Brissett from the New England Patriots for receiver Phillip Dorsett on Sept. 2. Brissett's first pass was a 50-yard completion to Moncrief. The Colts scored a touchdown two plays later to cut the Rams' lead to 37-9.
Brissett finished 2 for 3 passing for 51 yards. He led the Colts on their only touchdown drive of the game, recovered running back Marlon Mack's fumble in the end zone for a safety on the next possession and ended the afternoon with a three-and-out.
Despite his limited knowledge of the playbook after barely one week with the Colts, Brissett wouldn't use that as an excuse.
"I'm not going to sit here and make any excuses for me. I'm in the NFL, and you got to go out there and you got prepare like a starter,'' Brissett said.
"When your opportunity comes, you got to take advantage of it.''
Tolzien struggled to make throws outside the numbers, starting with his first pass intended for T.Y. Hilton.
Trumaine Johnson easily stepped in front of a deep out that was too long in the air, and he returned it 39 yards for the Rams' opening touchdown.
Lamarcus Joyner added a nearly identical touchdown on a 29-yard interception return in the third quarter, again on a pass that lacked velocity.
Tolzien said his arm was healthy and that the second pick-six error was not compounded by his earlier mistake.
"I wouldn't say I felt like things snowballed on my end,'' Tolzien said. "Now, obviously, if you're a fan watching at home, probably looked that way.''
Indianapolis does not have a timetable on Luck's return from his right shoulder surgery, which he underwent in January.
Colts coach Chuck Pagano defended the decision to sign Tolzien to a two-year contract in March over other quarterback options, most notably former San Francisco 49ers signal-caller Colin Kaepernick, despite the uncertain timetable for Luck.
"Never,'' Pagano said. "I'll never second-guess that. We made the right call.''
Pagano wouldn't say who would start at quarterback next Sunday in the Colts' home opener against the Arizona Cardinals but, he said, "We'll take a look at it.
"We got to look at everything,'' Pagano said after the Colts finished with 225 yards of offense and also lost a fumble.
The Associated Press contributed to this report.