Among his quips, he took a jab at those disappointed in his performance.
"Just the other day, Matt Damon -- I love the guy -- Matt Damon said he was disappointed in my performance. Well Matt, I just saw the 'Adjustment Bureau,' so, right back at you buddy," Obama said.
The president also targeted possible Republican presidential challenger Donald Trump, who was at the dinner.
This past week, the president released the long form of his birth certificate from Hawaii amid questions from Trump and others about where he was born.
"No one is happier, no one is prouder to put this birth certificate matter to rest than 'The Donald.' And that's because he can finally get back to focusing on the issues that matter, like, Did we fake the moon landing? What really happened in Roswell? And where are Biggie and Tupac?" Obama joked.
The president also showed a screen with his vision of how Trump could bring change to the White House. "Trump" was prominently displayed in glittery letters and girls could be seen with cocktails on a Jacuzzi-augmented front lawn.
Trump chuckled at some of the earlier jokes, but was clearly less amused as comedian Seth Meyers picked up where Obama left off.
"Donald Trump often talks about running as a Republican, which is surprising," said the Saturday Night Live actor, entrusted with providing some of the comedy for the evening. "I just assumed he was running as a joke."
On the serious side, Obama took time to thank the troops for their service overseas and noted that the people of the South, especially Alabama, have suffered heart-wrenching losses from the tornadoes.
The Associated Press contributed to this report.