Like his contemporary, Holiday Inn hotel-chain founder Kemmons Wilson, Isbell devised the idea of building and operating a chain of roadside motor hotels when, while on a cross-country trip with his wife Ingrid and their three children, he noted the substandard quality of roadside motor courts along US highways at the time. Route 66 at Flagstaff, Arizona in 1954 and set up its headquarters in Phoenix, Arizona, where the chain built the Sahara Hotel on North 1st Street downtown in 1956 (which later became the Ramada Inn Downtown) and a 300-room Ramada Inn in the 3800 block of East Van Buren in 1958 that would become the chain's flagship property and headquarters. Ramada opened its first hotel, a 60-room facility, on U.S. This first investment resulted in a rapid return on capital. Bill informed him of a hotel deal in Flagstaff, AZ that he was going to invest in and wanted to know if Marion would be interested in joining him. Isbell received a phone call from his brother-in-law, Bill Helsing.

Other original investors of Ramada Inns included Isbell's brother-in-law Bill Helsing Max Sherman, a produce operator from Chicago dubbed 'The Tomato King' Chicago attorneys Ezra Ressman and Mort Levin and Frank Lichtenstein and Robert Rosow of San Antonio, Texas.

Isbell (1905–1988) founded the chain in 1953 along with a group of investors including Michael Robinson of McAllen, Texas (who later went on to start Rodeway Inns in the early 1960s) and Del Webb of Phoenix (who owned the New York Yankees and went on to establish his own lodging chain, Hiway House, in 1956).

In the early days, Ramada had branded on-site restaurants and lounges. The friendly and balding Uncle Ben, on a Ramada Inn swizzle stick.

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Rooms at route 66 casino