She reached the checkpoint late Saturday afternoon, 52 minutes ahead of Martin Buser, who's gunning for his fifth championship.
Zirkle, 44, is trying to improve on two runner-up finishes the last two years and become the first woman to win the grueling 1,000-mile race since Susan Butcher in 1990. Besides Buser, a handful of other veterans are trying to reel her in.
Buser was the first musher into Kaltag, a village of 185 on the west bank of the Yukon River. He reached the village at 2 a.m. Saturday and rested for more than 3 1/2 hours.
Zirkle, 44, of Two Rivers, Alaska, pulled into Kaltag at 3:11 a.m. and chose not to rest her team in the village. Instead, she headed down the trail seven minutes later.
Buser departed Kaltag at 5:34 a.m., giving Zirkle a lead of two hours and 16 minutes.
Zirkle pulled into Unalakleet at 4:39 p.m. Saturday. She made the 85-mile run in 13 hours and 21 minutes, likely resting along the way for part of that time. She had been averaging nearly 11 mph, and a 13-hour run would have meant she averaged only 6.4 mph.
Zirkle and her husband, Allen Moore, train dogs at Two Rivers, Alaska, 24 miles west of Fairbanks. Zirkle takes the top dogs for the Iditarod.
The last championship for Buser, 55, a Swiss-born resident of Big Lake, Alaska, came in 2002. He has not finished in the top 10 since 2008, but he led most of Friday as teams made a 47-mile run on the wide Yukon River from Galena to Kaltag.
Zirkle is down to 11 dogs.
Buser left Kaltag with 14 dogs and reached Unalakleet in just under 12 hours, at 5:31 p.m.
Nicolas Petit of Girdwood, Alaska, left Kaltag in third place. He reached the village at 6:56 a.m., rested just 18 minutes and left at 7:14, nearly an hour and 45 minutes after Buser. But officials said he scratched at 6:45 p.m., 11 miles from Unalakleet, indicating that his team was fatigued. He was the rookie of the year in 2011 and finished a career-best 6th in the 2013 race.
Two mushers with decades of experience followed later Saturday morning.
Sonny Lindner, 64, who has completed 18 Iditarods since 1978, reached Kaltag at 6:30 a.m., rested for two hours and departed at 8:32 a.m. The best finish for the Two Rivers musher was second in 1981.
Four-time champion Jeff King, 58, of Denali, Alaska, reached Kaltag at 8:23 a.m. He stayed just nine minutes and followed Lindner out at 8:32 a.m.
Ten other mushers had left Kaltag as of 5:30 p.m., including former champions Robert Sorlie, Mitch Seavey and Dallas Seavey.
Unalakleet is 261 miles from the finish line in Nome.
The National Weather Service predicted mostly clear skies with lows of zero to 10 below and northeast winds of 10 to 20 mph for eastern Norton Sound and the Nulato Hills north of Unalakleet.