In a press release about the vandalism, park officials said it was the "worst case of damage to a cultural resource in the park's 60-year history."
Each year, hundreds of thousands of people hike up to the rock to see a panoramic view of the confluence of the Potomac and Shenandoah rivers, along with Harpers Ferry, park officials said.
Thomas Jefferson stood on the spot on Oct. 25, 1783.
He wrote of the view: "The passage of the Patowmac through the Blue Ridge is perhaps one of the most stupendous scenes in Nature. You stand on a very high point of land. On your right comes up the Shenandoah, having ranged along the foot of the mountain a hundred miles to seek a vent. On your left approaches the Patowmac in quest of a passage also. In the moment of their junction they rush together against the mountain, rend it asunder and pass off to the sea," according to the National Park Service's Web site.
Jefferson also said, "This scene is worth a voyage across the Atlantic."
Flynn said park officials are pursuing leads and working with the Jefferson County Sheriff's Department and the Harpers Ferry Police Department.
No arrests had been made.
Work to clean the rock has begin, with park officials using an acetone mixture. Samples of the paint have been taken to ensure the rock is restored to its natural state, Flynn said.
"It's certainly frustrating," Flynn said of the vandalism. "That's just a careless, thoughtless act."
While National Park Service rangers try to protect resources, access to the rock is not restricted. Keeping people away from the rock would hinder the Park Service's mission of allowing people to see important sites, Flynn said.
Jefferson Rock is "a victim that can't defend itself," she said.
The rock, which is listed on the National Register of Historic Places, consists of several large masses of Harpers shale piled upon one another, according to the National Park Service's Web site.
The uppermost slab of Jefferson Rock - the rock that was painted red - originally rested on a natural stone foundation so narrow that the rock could be swayed back and forth with a gentle push, the Web site says.
"Because this natural foundation had 'dwindled to very unsafe dimensions by the action of the weather, and still more, by the devastations of tourists and curiosity-hunters,' four stone pillars were placed under each corner of the uppermost slab sometime between 1855 and 1860," according to the Web site.
Anyone with information about the vandalism can call Flynn at 304-535-6232, or the National Park Service's dispatch office at 866-677-6677.