The brothers began designing engines in the early 1900s after Fred became involved in bicycle racing. In 1906 they formed the Mason Motor Car Company in Des Moines, Iowa, with funding from lawyer Edward R. Mason. The company later passed to F. L. and Elmer Maytag, who renamed it the Maytag-Mason Automobile Company before selling their stake in 1912.
The Duesenbergs relocated to Saint Paul, Minnesota, where they established Duesenberg Motors Company in 1913. Eddie Rickenbacker drove the first Duesenberg-designed race car at the Indianapolis 500 in 1914, finishing tenth. During World War I the brothers designed and built aircraft engines in Elizabeth, New Jersey. A Duesenberg driven by Tommy Milton won the 1919 Elgin Trophy.
In 1920 the brothers moved to Indianapolis, Indiana, and formally founded Duesenberg Automobile and Motors Company. Their racing program reached its peak that decade. A Duesenberg driven by Jimmy Murphy won the 1921 French Grand Prix — the first time an American car had won a major European Grand Prix. The company went on to win the Indianapolis 500 in 1922, when eight of the top ten finishers were Duesenbergs, and again in 1924, 1925, and 1927.
Alongside their racing work the Duesenbergs produced road cars of exceptional specification. The Model A, introduced from 1921, was powered by a 4.3-litre straight-eight engine producing 88 horsepower — the largest engine in any commercially available vehicle at the time — and was the first production car to feature hydraulic brakes on all four wheels. It also introduced an overhead camshaft and four-valve cylinder heads.
Transportation executive Errett Lobban Cord acquired the Duesenberg corporation in 1926. Under Cord's direction the company introduced the Model J in 1929, powered by a 265-horsepower straight-eight engine built by Lycoming and derived from Duesenberg's racing units. The engine used dual overhead camshafts and four valves per cylinder, making the Model J the most powerful American production car of its era. Bodies were custom-built by coachbuilders, with prices ranging from $14,000 to $20,000. Only the chassis and engine were supplied by the factory; the remainder was bespoke. Approximately 481 Model Js were produced before the company was dissolved.
The supercharged SJ variant, introduced in 1932, reportedly reached 104 mph in second gear and exceeded 135 mph at its top end — performance figures that contemporaries found difficult to believe. Only 36 SJ units were built. Two further-modified SSJ roadsters were produced in 1935 for actors Gary Cooper and Clark Gable; Cooper's car sold at auction in 2018 for $22 million, making it the most expensive American car ever sold at auction at that time.
Historian Donald Davidson described the Duesenberg as the "most prestigious passenger car" in American history, likening it to an American Rolls-Royce. The cars were favored by movie stars, royalty, and wealthy industrialists.
Van Zandt, one of the early promoters who had signed over naming rights and patents, left the company in 1921. Duesenberg entered receivership in 1924 before the Cord acquisition. Cord later sold the corporation, which was formally dissolved in 1937. The last car produced by the original company was completed in 1940, commissioned by German artist Rudolf Bauer and finished by August Duesenberg after the factory had already closed.
Several revival attempts followed. August Duesenberg failed to restart the company in 1947. A 1966 concept car by his son Fritz and designer Virgil Exner came to nothing. Bernard Miller purchased the Duesenberg Corporation in 1970 and produced eight SSJ models using original body templates before the venture closed in 1974. A further revival beginning in 1978 under the name Duesenberg Motors Company produced sixty-seven handmade "Duesenberg II" automobiles styled after the 1920s and 1930s originals before closing in 2001.
The Duesenberg brothers popularized the straight-eight engine and four-wheel hydraulic brakes in American road cars, and their racing achievements established American credibility on the international stage during a period when European manufacturers dominated the sport. The Model J engine's influence on subsequent high-output designs — with Randy Ema writing that it "single-handedly started the horsepower race that drove the number of cylinders from twelve to sixteen" — outlasted the company itself. The Auburn Cord Duesenberg Automobile Museum in Auburn, Indiana, preserves their heritage.