The Argentine hot-shot poured in a season-high 46 points with a career-best eight three-pointers, leading the San Antonio Spurs over the Cavaliers 112-105 on Wednesday night.
After Ginobili torched the Toronto Raptors for 34 points and a career-high 15 rebounds on Monday night, the sweet-stroking lefthander followed it up with the second highest scoring outburst of his career.
"It was a special game," said Ginobili, who connected on 15-of-20 floor shots and eight-of-11 from behind the arc. "I was feeling good from the beginning. I felt like every shot was going to go in and it did."
Tim Duncan had 23 points with 13 rebounds for the travel-weary Spurs (34-17) who finished 6-3 on their season-long nine-game road trip.
"I'm just happy he's on my team," Duncan said. "He's unbelievable when he gets rolling like that. The funny part is, I've seen him do it before."
Trailing by four entering the final frame, the Spurs shot a sizzling 14-of-16 from the field. Ginobili led the way with 18 points, including four triples, as the defending champions outscored their hosts 41-30.
"Manu Ginobili is a bad boy," Cavaliers head coach Mike Brown said. "He had a night tonight."
League top scorer LeBron James led Cleveland (29-23) with 39 points, including 18 in final 12 minutes, along with nine assists. Larry Hughes chipped in with 26 points.
"It was unbelievable," James said. "There's nothing you can do when a guy gets hot like that. It was a great performance by Manu."
Elsewhere: Boston Celtics 111, New York Knicks 103 Paul Pierce scored 24 points, newly-named All-Star teammate Ray Allen had 21 and the league-best Celtics (41-9) rolled to their fifth straight victory.
Allen was named to replace injured Washington Wizards' forward Caron Butler on the Eastern Conference squad for Sunday's All-Star Game in New Orleans.
Jamal Crawford led the Knicks (15-37) with 26 points.
Detroit Pistons 96, Indiana Pacers 80 Richard Hamilton, Chauncey Billups and Tayshaun Prince scored 14 points apiece as the host Pistons rolled into the All-Star break with a 10-game winning streak.
Houston Rockets 89, Sacramento Kings 87 Steve Novak nailed a three-pointer - his only points of the game - with 2.5 seconds left, lifting the Rockets to their eighth straight victory and 17th in the last 20 games.
Yao Ming led Houston (32-20) with 25 points and 14 rebounds. Ron Artest topped Sacramento (23-28) with 30 points.
LA Lakers 117, Minnesota Timberwolves 92 Kobe Bryant scored 29 points, Lamar Odom had his 12th career triple-double, helping the Lakers end their longest road trip of the season at 7-2.
The Lakers received 19 points with nine rebounds from Spain's Pau Gasol while Odom finished with 10 points, 16 rebounds and 10 assists. Al Jefferson collected 19 points and nine rebounds in the Timberwolves' (10-41) fifth consecutive loss.
Orlando Magic 109, Denver Nuggets 98 Rashard Lewis scored 25 points while Dwight Howard had 23 points with 24 rebounds and the Magic snapped the Nuggets' three-game winning streak.
Carmelo Anthony led Denver (32-20) with 32 points before fouling out late in the final quarter.
Dallas Mavericks 96, Portland Trail Blazers 76 Dirk Nowitzki scored a season-high 37 points, helping the host Mavericks stop a two-game slide.
Toronto Raptors 109, New Jersey Nets 91 Chris Bosh scored 27 points, Spain's Jose Calderon had 22 with 12 assists and the Raptors routed the Jason Kidd-less Nets.
Kidd was with the team but placed on the inactive list while awaiting word from the league office on a proposed multi-player deal, which would send the eight-time All-Star point guard to Dallas.
Golden Stte Warriors 120, Phoenix Suns 118 Monta Ellis scored 37 points, including two free throws with 2.7 seconds left, and the Warriors escaped when Leandro Barbosa bounced a potential game-winning three-pointer off the rim at the final buzzer.
Amare Stoudemire scored 29 points, Grant Hill had 26 with 15 boards for Phoenix (36-16) which decided recently-acquired Shaquille O'Neal was not ready to make his Suns' debut.
Philadelphia 76ers 102, Memphis Grizzlies 88 Andre Iguodala had 29 points, eight rebounds and eight assists, sending the Sixers to their fifth straight win while handing the Grizzlies their ninth consecutive road loss.
Charlotte Bobcats 100, Atlanta Hawks 98 (OT) Emeka Okafor had 20 points with 22 rebounds and Jeff McInnis' hit the game-winning basket with 51.4 seconds left in overtime as the Bobcats broke a seven-game slide.
New Orleans Hornets 111, Milwaukee Bucks 107 Peja Stojakovic scored 19 points, including a three-pointer with 15 seconds left, and the Hornets headed home to host NBA All-Star Weekend atop the Western Conference standings.
David West netted 22 points for New Orleans (36-15) and All-Star teammate Chris Paul had 21 and 10 assists. Michael Redd led Milwaukee (19-34) with 30 points.
Utah Jazz 112, Seattle SuperSonics 93 Carlos Boozer posted his first career triple double with 22 points, 11 rebounds and 10 assists, leading the visiting Jazz to its 12th win in the last 13 games.
Washington Wizards 91, LA Clippers 89 Antawn Jamison scored 29 points, including a tip-in with three tenths of a second left, helping the visiting Wizards snap a season-high eight-game slide.
By Paul Levine, dpa