The resort is named after Chief Nemacolin, a native Delaware Indian who in 1740 trailblazed a route through the Laurel Highlands mountains between what is now Cumberland, Maryland and Brownsville, Pennsylvania. Pittsburgh industrialist Willard Rockwell established a private game reserve on the property called Nemacolin Trails Hunting Reserve in 1968. The Rockwells established a hunting lodge along with a golf course and airstrip. Lakes Louise and Carol were added and Beaver Creek was developed and stocked into a trout fishing stream. In September 1970, the hotel was opened to the public under the name Nemacolin Inn. In 1979, the property was sold to Cordelia Scaife May, but was returned three years later to the Rockwell family when Kent Rockwell repurchased the property and opened it to the public. By 1987, the 400 acre complex consisting of one hotel and a nine hole golf course was in bankruptcy. Joseph A. Hardy III, founder of the 84 Lumber Company, bought Nemacolin at an auction that year and reopened the complex as an upscale hotel and resort. In the following years Hardy expanded the property to encompass 2000 acres. In 2002, Hardy transferred full ownership of the resort to his daughter, Maggie Hardy Magerko. In 2007, Nemacolin's boutique hotel, Falling Rock, received AAA Five Diamond status. In 2009 Nemacolin's fine dining restaurant, Lautrec, received a Five Star rating from the Forbes Mobile Travel Guide and held that distinction until 2015. In 2008, the resort housed the largest wine cellar in Pennsylvania with a collection of approximately 17,000 bottles. On July 1, 2013, Isle of Capri Casinos opened Lady Luck Casino Nemacolin on the property, under a lease agreement with the resort. The casino operated under a Pennsylvania Class 3 "resort" gaming license, meaning that casino patrons had to first be customers of Nemacolin in order to access the casino floor--either by staying overnight at the resort, purchasing an annual membership, or purchasing a $10 resort gift card. In 2019, Churchill Downs Inc. bought the casino operating business for $100,000 from Eldorado Resorts. In June 2019, Churchill paid a fee of $1 Million to the Pennsylvania Gaming Control Board to eliminate the access fee requirement, allowing the general public to enter the casino at no additional charge.
Nemacolin Woodlands became host to PGA Tour event the 84 Lumber Classic in 2003. Contested on Nemacolin's Mystic Rock golf course, the event came to an end in 2006. The four winners of the 84 Lumber Classic tournaments held on Mystic Rock at Nemacolin Woodlands Resort were:
