Nemanja Vidic (28), Cristiano Ronaldo (45), Wayne Rooney (75, 79) and Darren Fletcher (78) scored for Alex Ferguson's men, while Masato Yamazaki (74), Yasuhito Endo (85) and Hideo Hashimoto (90) netted Gamba's goals.
The Red Devils broke the deadlock when Vidic beat the Gamba defense to head Ryan Giggs corner into the back of the net.
In the first half's injury time, United added a copycat second, but this time Giggs' corner was met by the head of Ronaldo.
Gamba Osaka got back in the tie after the interval thanks to Yamazaki's strike following a lovely team move from the Japanese outfit.
It didn’t take longer than one minute for substitute Rooney to restore his team's two-goal lead after latching on to Fletcher's pass.
The scot turned from provider to scorer moments later when he headed Patrice Evra's cross in the back of Fujigaya's net.
Rooney doubled his tally on 79 minutes after being released through a brilliant Giggs past.
However, Gamba refused to surrender without a fight, and their cause was helped when they were awarded a penalty after the ball hit Gary Neville's hand in the box.
Endo stepped up and successfully converted from the spot.
In the game's last minute, Hashimoto netted Gamba's fourth with a left-footed effort from inside the United area, to finish the game in a what can be seen as an honorable defeat to the European champions.
United will now be facing Liga de Quito of Ecuador in the competition's final, while Gamba Osaka will clash with Pachuca for the third/fourth place game.