With the victory, the Lakers extended their home winning streak to seven games.
O'Neal and Bryant combined to make 28-of-49 shots and dominated the second half, scoring 40 of the Lakers' 52 points. Meanwhile, the Timberwolves' Kevin Garnett struggled. He was held to just 15 points on 6-of-17 shooting, and he was hounded by Lakers forward Mark Madsen down the stretch.
"I haven't really matched up with Garnett that much," Madsen said. "It wasn't going to be an individual effort, it was going to be a team effort. That's what happened tonight, it was a collective team effort to try to slow him down. You can never contain him, but you can try to slow him down a bit."
"Madsen did a great job," O'Neal said. "His energy boosts up the bench. We like to see him in there. He's spent a lot of time, worked hard, he's going to be our key."
Minnesota trailed the entire fourth quarter, but pulled to within 89-83 on a three-pointer by former Laker Anthony Peeler with 6:05 remaining. Bryant, who made 12-of-24 shots from the floor, responded with a jumper to spark a decisive 9-0 run.
O'Neal had a layup and made 1-of-2 free throws before Bryant sank a pair from the line. O'Neal capped the spurt with another layup for a 98-83 cushion with 3:35 to go.
As the Lakers took control, the T'Wolves missed four consecutive shots, including two by Garnett, who was held to just three points in the fourth quarter.
Madsen drew an offensive foul on Garnett, but played stellar defense on the All-Star forward, who was so frustrated he got into a shoving match with Robert Horry with 1:49 remaining.
"Kevin tried the muscle game, but Mark is strong," said Lakers Coach Phil Jackson. "One thing for sure about him is he has the strength to hold the block down there."
O'Neal had a pair of alley-oop dunks just 47 seconds apart in the final three minutes as the Lakers cruised to their eighth win in nine games.
He had his most dominant performance in a season riddled by injuries, He made 16-of-25 shots, and had five blocks and four assists.
"I feel pretty good," said O'Neal, who has been plagued by foot and knee problems throughout the season. "My fellows were looking for me today. They really didn't double me. I took the high percentage shots like I usually do."
Rick Fox scored 13 points, and Madsen had a season-high 10 and six rebounds as Los Angeles (34-26) moved a season-high eight games over .500.
"I was really (ticked) off that he had 10 points off me," Garnett said of Madsen. "I am a defender that really enjoys to see whoever I am playing not score, so I was really ticked off. He plays with a lot of energy and I knew that coming into the game, but that still does not take away from the fact that he was scoring, and that isn't going to make me feel any better."
The Lakers grabbed 18 offensive rebounds, scored 54 points in the paint, and committed a season-low five turnovers.
Rasho Nesterovic scored 19 points and Peeler finished with 15 for the Timberwolves, who have lost three straight on the heels of a seven-game winning streak.
Minnesota shot 51 percent (38-of-75) from the floor, but was just 15-of-22 from the line, and turned the ball over 15 times.