The first test is scheduled for 12:30 p.m. Thursday and will last for three minutes.
Power plant owner Exelon says the sirens have improved sound and better battery backup to ensure they'll work during an electrical outage.
Ninety-six sirens are scattered throughout communities within a 10-mile radius of the facility near Harrisburg. Three more tests are planned through mid-November.
Sixteen sirens in Lancaster County did not sound during a test last year due to a timing glitch, which was later remedied.
The partial meltdown of a Three Mile Island reactor in 1979 is considered the worst commercial nuclear power plant accident in U.S. history.