O'Neal sparked the Lakers to an early 23-point lead and then was the key ingredient in the late stages as Los Angeles held on to down the Nets, 99-94.
The Nets walked away from their first game ever in an NBA Finals feeling they could compete with the Lakers since New Jersey outscored Los Angeles in each of the last three quarters. But it was still a Lakers' win and leaves them needing just three more for their third straight league title.
O'Neal scored 35 points, including 10 of his team's first 23 and 11 of its last 20. He claimed 16 rebounds, blocked four shots, committed just two fouls and made 12 of 21 free throws.
"We started the game with the same intensity and focus we had at the end of the last series," said the Lakers' Kobe Bryant, referring to his team's comeback from a 3-2 deficit in the Western Conference finals against Sacramento.
"Then we kind of let it die down. But we just felt we had to get back to basics. We pounded the ball inside and let Shaquille take us home."
The Nets took heart that they climbed back in the game, closing to within three points at one stage in the fourth quarter.
"I don't think guys were nervous in the first quarter," said New Jersey's Kenyon Martin. "We just didn't make shots. You take away the first quarter and we were all right. We just dug too big a hole and couldn't get out of it.
"We played well for three quarters. I think that will gives us confidence for the second game."
Game 2 will be played Friday night in Los Angeles, after which the series will move to New Jersey for three games if needed.
New Jersey rallied behind Jason Kidd's triple double, the first in an NBA Finals in nine years. He had 23 points, 10 rebounds and 10 assists.
"That's what Jason does," Bryant said. "It would be different if a guy is trying to score 40 or 50 points. You can shackle a guy like that. But he is all over the place, shooting the ball and getting other guys shots."
The Lakers came very close to having their season halted by Sacramento and they came out Wednesday night with a purpose.
During the first 10 minutes, O'Neal made five of seven shots and had three blocks. He went to the bench for a lengthy rest with his team owning a 25-10 lead and when he came back in the second quarter, he hit his seventh and eighth consecutive field goal attempts to boost the Lakers' advantage to 42-19.
During one point in Los Angeles' hot start, the Lakers hit nine shots in a row. The Nets made only six field goals in 22 tries during the opening quarter and not once in the first 18 minutes could they score more than two points in a row.
But over the closing six minutes of the half, the Nets went on a 17-6 run to get within 48-36 at intermission. And after the break, Keith Van Horn hit two quick three-pointers to keep the New Jersey comeback going.
"I thought they (his team) played on cruise control after we got off to the good start," said Los Angeles coach Phil Jackson, who is trying for his ninth NBA title. "The Nets got some momentum and got some great second-chance opportunities."
The Nets, however, never had an answer for O'Neal. For most of the game, the Nets tried to cover the massive center with just one man.
"We wanted to attack them inside," Jackson said. "It is always a shock to have to play Shaq, especially when they weren't giving their inside guys much help."
When Martin put in an offensive rebound, was fouled and made the free throw for a three-point play, the Nets had closed within four points midway through the third quarter. Los Angeles spent the rest of the contest fighting off the Nets, who trailed by four with 1:50 to go.
O'Neal then hit two free throws and he next rebounded a big miss by Kidd that led to a basket by Rick Fox with just over a minute remaining that all but wrapped up the contest.
Bryant added 22 points for the Lakers and Fox had 14. Martin contributed 21 for the Nets.
"We just got a little lackadasical," O'Neal said. "We didn't know much about this team and we know more about them now. We messed around. We need to pick it up and we will."
Free throws were a major factor since Los Angeles took 19 more than did the Nets and made 17 more. New Jersey made only 15 of 26 from the line and shot only 39 percent from the field. Martin was seven of 22 and Van Horn made just five of 14.