The 45-year-old bypassed Jeff King who pulled into the village about two hours before her.
Zirkle is trying for her first win after finishing second in the last three years. If she pulls in to the finish line at Nome first, she would be the first female Iditarod winner since 1990 when the late Susan Butcher finished first.
Zirkle hasn't taken her eight hour layover yet this race. King, who has won the Iditarod four times, has taken his.
Rounding out the top five are Mitch Seavey, who also reached Koyukuk, Aaron Burmeister and Dallas Seavey.
Koyukuk is 667.9 kilometres from Nome.
Two mushers scratched Saturday. Gerald Sousa dropped out at Galena and Christine Roalofs left in Ruby. Both cited the best interests of their teams.
The race started Monday with 78 mushers in Fairbanks. Four mushers have scratched and one has been disqualified. Two dogs have died, including a dog on four-time champion Lance Mackey's team.