Unlike his chimp grandfather who became famous flying into outer space, Ham III (voice of ANDY SAMBERG) toils away in relative obscurity being fired out of a circus cannon while his handler and grandfather's friend, Houston (voice of CARLOS ALAZRAQUI), looks on in disappointment. Ham III isn't looking for much in his life, but the latter changes when the interstellar Infinity Probe -- designed to look for life elsewhere in the galaxy -- is sucked into a wormhole and then lands on the planet Malgor. There, it falls into the hands of cantankerous buffoon Zartog (voice of JEFF DANIELS) who uses its advanced robotic features to intimidate the Malgorians into becoming his slave labor.
Back on Earth, the Senator (voice of STANLEY TUCCI) is upset about the missing probe and threatens to shut down the space program if it can't be found. Knowing it's possibly too dangerous to send humans through the untested wormhole, a trio of scientists -- Dr. Jagu (voice of OMID ABTAHI), Dr. Bob (voice of PATRICK BREEN) and Dr. Smothers (voice of KATH SOUCIE) -- decides it would be best if chimps were sent into it first.
Luckily for them, they have a group at the ready, including flight commander Titan (voice of PATRICK WARBURTON), Lt. Luna (voice of CHERYL HINES) and young but eager Comet (voice of ZACK SHADA). The latter doesn't get the chance, however, since the Senator wants the mission to be high profile, thus resulting in Ham III filling the last spot.
He views it all as a joke and his fight crew thinks the same of him, but soon they're hurtling into outer space, through the wormhole, and onto Malgor. When Zartog learns of this new machine from the sky, he sends his minions to retrieve it, unaware that Titan is still inside, thus leaving Luna and Ham III stranded. As they try to make their way to Zartog's fortress, they must deal with various hazards along the way, some of them introduced by the small Kilowatt (voice of KRISTIN CHENOWETH) whose huge head glows whenever she's frightened.