Grand Hotel opened in 1887, billed as a summer retreat for vacationers who arrived on Mackinac Island by lake steamer from Chicago, Erie, Montreal and Detroit, and by rail from across the continent. The property's 600-foot front porch soon became the principal meeting place for all of Mackinac Island, as well as a promenade for the elderly and a "Flirtation Walk" for island romantics.

Increasing popularity required the addition of the West Wing in 1897, but the island's popularity reached a kind of fever pitch as turn-of-the-century automobiles found their way onto the island. A law banning cars was soon passed, but wasn't enforced until the 1930s. In 1933 W. Stewart Woodfill, who had been hired as a desk clerk in 1919, purchased the hotel and becomes sole owner. Two years later, a radio salon was added, where patrons could listen to Jack Benny and other popular programs.

In 1976 R.D. Musser, who joined the hotel staff in 1951, and his wife Amelia began redesigning the hotel's interior and exterior with the help of architect Richard Bos and decorator Carleton Varney. In 1979 the Mussers purchased Grand Hotel. In 1998, six new named rooms opened in the West Wing in honor of first ladies Barbara Bush, Lady Bird Johnson, Betty Ford, Rosalynn Carter, Nancy Reagan and Barbara Bush. Two new two-bedroom suites, the Grand and the Carleton Varney, were also added.

Two years later, the expansion started up again, as construction began on the Millennium Wing, which included a 300-seat addition to the Main Dining Room and 42 new guest rooms. The Millennium Wing opened in 2001 on the east end of the hotel, featuring 42 new guest rooms and The Grand Pavilion, a 3,600-square-foot private meeting room and dining room. In 2003, the modest Masco Cottage, a four-bedroom retreat, was added to the east end of the hotel, bringing the total number of guest rooms to 385.