Cheney, who has struggled to gain traction against the incumbent, cited health issues in announcing her decision to abandon the race.
“Serious health issues have recently arisen in our family, and under the circumstances, I have decided to discontinue my campaign," Cheney said in a statement to The Hill early Monday. "My children and their futures were the motivation for our campaign and their health and well being will always be my overriding priority."
The few public polls of the race have found Enzi with a huge lead.
Cheney's campaign, for its part, suffered setbacks and missteps almost from the beginning.
Her campaign has won the most attention for creating a very public rift within the close-knit Cheney family.
After conservative groups worked to paint Cheney as soft on social issues, her push to show she opposed legalizing gay marriage deeply offended her sister, Mary Cheney, who is openly gay. The tension exploded onto Facebook, where Mary and her wife attacked Liz's views on the matter.
Cheney has also faced accusations of carpet-bagging since she moved back to the state in 2012 from Virginia. Some have also questioned the decision to challenge Enzi, who is seen as having a conservative voting record.
That record also left Cheney with few areas to attack the incumbent.
Cheney had gotten off to a strong fundraising start for the race, but hadn't won much support from Washington-based conservative organizations that often fuel right-wing primary challenges. Groups like the Club for Growth and Senate Conservatives Fund stayed out of the race.
Enzi improved his own fundraising efforts once Cheney entered the race, and won the support of the American Principles Fund, a socially conservative group run by former Arkansas Gov. Mike Huckabee's (R) daughter that had aired ads backing him and bashing Cheney.
Cheney didn't specify what health issues were forcing her to leave the campaign in her statement.
"Phil and I want to thank the thousands of people in Wyoming and all across the country who have supported my campaign," she added. "As a mother and a patriot, I know that the work of defending freedom and protecting liberty must continue for each generation. Though this campaign stops today, my commitment to keep fighting with you and your families for the fundamental values that have made this nation and Wyoming great will never stop.”
—This post was originally published at 12:28 a.m. and last updated at 9:20 a.m.