The flyby of the Juno spacecraft, surveilling the 10,000-mile-wide (16,000-kilometer-wide) storm, is scheduled for 9:55 pm Monday (0155 GMT Tuesday).
"Jupiter's mysterious Great Red Spot is probably the best-known feature of Jupiter," said Scott Bolton, principal investigator of Juno from the Southwest Research Institute in San Antonio.
"This monumental storm has raged on the solar system's biggest planet for centuries."
The storm looks like a churning red knot on the planet's surface. It has been monitored since 1830, and may have existed for more than 350 years, the US space agency said.
Equipped with instruments that can penetrate clouds to measure how deep the roots of this storm go, scientists hope to learn more about the workings of the raging tempest.
All eight of Juno's instruments, including its camera, will be on when the spacecraft passes about 5,600 miles (9,000 kilometers) above the Giant Red Spot clouds, NASA said.
Juno launched from Cape Canaveral, Florida in August, 2011, on a mission to learn more about Jupiter's origins, structure, atmosphere and magnetosphere.