She is seeking to become the first woman to win since the late Susan Butcher claimed victory in 1990.
Zirkle was first to leave the Ophir checkpoint Wednesday, 432 miles (695 kilometers) into the race.
Earlier Wednesday, Frenchman Nicolas Petit retook the lead after arriving first at Ophir when defending champion and front-runner Joar Ulsom stopped for a 24-hour mandatory rest at Takotna.
Participants also must take two eight-hour rests.
The race began Sunday north of Anchorage. The winner of the 1,000-mile (695-kilometer) race is expected in Nome on Alaska’s western coast next week.
Musher Shaynee Traska of Gladwin, Michigan, scratched in Nikolai out of the best interest of her team, leaving 51 mushers in the race.