In a flashback to 41 B.C.E., Cleopatra, Virginia Madsen, visits her tomb beneath the Sphinx to bury a treasure and form an undead army to protect it, sealing a curse that promises petrification to those who dare disturb it.
In the present, Mindy Cohn as Velma Dinkley leads an archaeological team to restore the ancient landmark, uncovering an ancient necklace and stumbling upon Cleopatra’s tomb. At the same time, Mystery Inc. fans out to Egypt for a surprise reunion: their van—the Mystery Machine—breaks down in the desert, but help arrives from Amahl Ali Akbar, with his hawk Horus, in addition to meeting Jeremy Piven as Rock Rivers, the former Fear Facers host whose show was canceled after a scandal of faked footage. The crew presses on toward the tomb, while Velma’s friends make their way to the site and Velma reconnects with her allies.
Their path is blocked by a heavy-handed treasure hunter named Dr. Amelia Von Butch, portrayed by Christine Baranski. Despite Velma's pleas that Cleopatra’s curse will turn anyone who enters the tomb to stone, Amelia’s team detonates the entrance with explosives. A freak sandstorm seals the chamber, and the expedition discovers Omar—Prince Omar, played by Ajay Naidu—seemingly petrified within. Yet Amelia’s crew pushes forward while Fred Jones begins to solve the mystery, and Velma reluctantly agrees to follow, only to be separated from the others by a trap that splits Shaggy Rogers and Scooby-Doo from the group.
As the undead army marches, Velma appears to be petrified, and the others race to recover the ancient necklace from Amelia’s grasp. They reunite with the others, only to be attacked by Cleopatra herself, now a revenant. Fred and Daphne Blake escape outside toward a bustling bazaar, while Amahl helps them regroup. Back in the main chamber, Amelia captures Daphne, and Cleopatra closes in on the others. Amahl spots a path to safety and joins the pursuit, while Fred devises a plan to end the curse.
Returning to the heart of the tomb, Mystery Inc. discovers Amelia has captured Velma’s truth and learns that the undead army is composed of Omar’s workers, not a legion of the dead, and that the petrified figures were statues. Velma reveals that Omar recruited her to help stop Amelia and to secure historical protection for the tomb, while Rivers’s footage secures a promise of preservation.
With Amelia’s capture and Omar’s team continuing the restoration, the climax unfolds as Daphne—dressed as Cleopatra—leads the lost-city’s citizens into battle against the petrified army. Amid the chaos, Amelia wins a temporary upper hand by stealing Cleopatra’s crown, but the Nile erupts, flushing the tomb’s riches into the world outside. In the aftermath, Velma’s true role is exposed, Amelia and her crew are arrested, and Omar’s crew completes the Sphinx restoration.
In the final moments, a lighter misstep by Shaggy (who ultimately triggers a large firecracker) results in the Sphinx nose being blown away, a moment that Omar calls an odd improvement in appearance, while Mystery Inc. secures the relics and ensures the tomb’s enduring protection. The adventure closes with a renewed balance between history and guardianship, and the team heads home, having exposed the truth behind the curse and the treasure they sought.
