Lyles, who saw his ERA increase to 3.50 from 2.66, had control problems from the outset. He issued first-inning walks to Everth Cabrera and Smith before giving up a two-two-run double to Yonder Alonso.
"I just didn't throw enough strikes," Lyles said. "Too many balls, too many strikes. I'm not going to be successful like that. You can't put guys on base that many times. It's just one of those things you learn from. Turn the corner and get better from it."
Tulowitzki, who had three hits, answered in the bottom of the first with his NL-leading 12th homer of the season.
But Smith, who played for the Rockies from 2007-11, made it 4-1 San Diego in the second. One out after Chris Denorfia doubled, Smith drove a 1-1 offering from Lyles over the center field fence for his fourth home run of the season.
The Rockies pulled to 6-3 on Gonzalez's sacrifice fly in the fourth and Jordan Pacheco's RBI single in the fifth.
"Just a tough night," Rockies manager Walt Weiss said. "We fought back. I think everyone thought we'd end up winning that game but we came up short."
NOTES: San Diego right-handed reliever Donn Roach (1-0) will start Sunday's series finale against the Rockies in place of Andrew Cashner, who was placed on the 15-day disabled list because of soreness in his pitching (right) elbow. Roach be opposed by Colorado's Juan Nicasio (4-2). ... The Padres recalled RHP Kevin Quackenbush from Triple-A El Paso to fill Cashner's roster spot. ... Lyles' previous career high for walks was five against Boston on July 3, 2011, while with Houston. ... The pinch homer was the fourth of Quentin's career and the fifth by a Padre this season, most in the majors. ... Weiss said Brandon Barnes was unavailable Saturday because of a stomach illness.