Regular kid Nat (voice of TREVOR GAGNON), brainy IQ (voice of PHILIP DANIEL BOLDEN) and food-obsessed Scooter (voice of DAVID GORE) are lifelong friends who just so happen to be talking houseflies. Nat feels like his life is boring, especially compared to the events from his Grandpa's (voice of CHRISTOPHER LLOYD) many years, including flying with Amelia Earhart on her transatlantic solo trip.
Believing in his grandpa's motto "If it ain't an adventure, it ain't worth doing," Nat concocts the idea that he and his friends stow away onboard the Apollo 11 spaceflight to land a man on the moon. With a little convincing, they agree, and soon are headed toward the lunar body, much to the horror of the boys' moms, including Nat's (voice of KELLY RIPA), who didn't inherit Grandpa's sense of adventure.
They're not alone, however, in showing surprise about the stowaways. Not wanting them to be the first flies on the moon, Russian General Poopchev (voice of ED BEGLEY, JR.) and Grandpa's long-lost love, Nadia (voice of NICOLLETTE SHERIDAN), order their inside fly at Cape Canaveral, Yegor (voice of TIM CURRY), and his two goons to try to sabotage the trip.
From the approach, landing and then return toward Earth, Nat and his friends experience the thrills and perils of space travel, all as Grandpa and others race to stop Yegor and his thugs from endangering the young flies' lives.