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In 1915 Carl Eric Wickman joined forces with Ralph Bogan, to form the Mesaba Transportation Company.

By the end of World War I in 1918, Wickman owned 18 buses and was making an annual profit of $40,000. In 1922, Wickman joined forces with Orville Caesar, the owner of the Superior White Bus Lines. Four years later, Wickman purchased two West Coast operations, the Pioneer Yelloway System (the operator of the nation's first transcontinental bus) and the Pickwick Lines, creating a national intercity bus company.

The Greyhound name had its origins in the inaugural run of a route from Superior, Wisconsin to Wausau, Wisconsin. While passing through a small town, Ed Stone, the route's operator, saw the reflection of his 1920s era bus in a store window. The reflection reminded him of a greyhound dog, and he adopted that name for that segment of the Blue Goose Lines. The Greyhound name became popular and later applied to the entire bus network. Stone later became General Sales Manager of Yellow Truck and Coach, a division of General Motors (GM), which built Greyhound buses. Wickman, as the president of the company, continued to expand it so that by 1927, his buses were making transcontinental trips from California to New York. In 1928, Greyhound had a gross annual income of $6 million.

In 1929, Greyhound acquired additional interests in Southland Transportation Company, the Gray Line, and part of the Colonial Motor Coach Company to form Eastern Greyhound Lines. Greyhound also acquired an interest in Northland Transportation Company, and renamed it Northland Greyhound Lines.

By 1930 more than 100 bus lines had been consolidated into what was called the "Motor Transit Company." Recognizing that the company needed a more memorable name, the partners of the Motor Transit Company decided to rename it after the "Greyhound" marketing phrase used by earlier bus lines.

Wickman's business suffered during the Great Depression, and by 1931 was over $1 million in debt.

As the 1930s progressed and the economy improved, the Greyhound Corporation began to prosper again. In 1934, intercity bus lines (of which Greyhound was the largest) carried approximately 400,000,000 passengers - nearly as many passengers as the Class I railroads. The 1934 hit film, It Happened One Night, the first movie to win the Big Five Academy Awards, centered on an heiress traveling by Greyhound bus. The movie is credited by the company for spurring bus travel nationwide. In 1935, national intercity bus ridership climbed 50% to 651,999,000 passengers, surpassing the volume of passengers carried by the Class I railroads for the first time.

To accommodate the rapid growth in bus travel, Greyhound also built many new stations in the period between 1937 and 1945, most of them in a late Art Deco style known as Streamline Moderne. In 1937, Greyhound embarked on a program of unifying its brand identity by acquiring both buses and terminals in the Streamline style. By the outbreak of World War II, the company had 4,750 stations and nearly 10,000 employees.