In the mid-20th century, Fort Wayne was a major manufacturing center of the northeastern United States. Major employers included General Electric (which was a merger of many electric companies including Fort Wayne's Jenny Electric), International Harvester (left Fort Wayne in 1983), and Tokheim gasoline pumps (sold in 2003). Phelps Dodge, Rea Wire, and Essex Wire comprised the largest concentration of copper and enamel wire manufacturing in the world. In the latter half of the 20th century, shifts in manufacturing patterns led to the reduction of the number of manufacturing plants and jobs, and Fort Wayne could be counted among the relatively stagnant "rust belt" cities of the northeast.

The Fort Wayne region has always been prominent in the automotive industry. John Lambert of nearby Ohio City, Ohio built the first gasoline-powered automobile in the U.S. in 1891. The Auburn, Cord, and Duesenberg were manufactured in nearby Auburn, Indiana. International Harvester Corporation manufactured trucks in New Haven, Indiana from 1910 until 1982, and produced the Scout, one of the first SUVs.

To support these many manufacturers, OEM manufacturers sprung up. Bowser, inventor of the gas pump, actually predated automobiles, manufacturing in Fort Wayne from 1885 to 1962. Other area factories manufacture a wide variety of components ranging from wheels to steering wheels, from transmissions to automotive trim, from hydraulic hoses to nuts and bolts.

Dudlo Wire opened on Fort Wayne's Wall Street in 1912, and a decade later, was the world's largest manufacturer of magnet wire, selling to the likes of Delco-Remy and Ford Motor Company. Dudlo was bought by General Cable Corporation, with Fort Wayne operations were closing in 1933 - but Dudlo's general manager in Fort Wayne, Victor Rea, opened his own factory in a new location as Rea Magnet Wire, and Essex Wire Corporation opened up in the old Dudlo factory. In turn, to support the wire companies, other companies sprung up manufacturing diamond dies for drawing copper wire.

In recent decades growth based on a more diverse economy has resumed. General Motors opened the Truck and Bus Assembly operation in the 1980s. Fort Wayne employs many in the transportation and logistics sector, with Sirva, the Norfolk Southern Railway, along with its subsidiaries Triple Crown Services (supplying intermodal services) and TransWorks (supplying carrier and shipper transportation tools), and Kitty Hawk Air Cargo combining for more than 2,500 local jobs. National defense is also an increasingly important component of the local economy, with ITT and Raytheon employing more than 1,000 people each.

Mid-Size businesses have also shown growth throughout the Fort Wayne area. Insurance companies such as K&K Insurance, Brotherhood Mutual Insurance Company, and Insurance & Risk Management, one of Indiana's largest private insurance companies, have their headquarters in the Fort Wayne area. The finance sector has grown in recent years as well, having accounting firms such as Baden Gage and Schroeder and the bank headquarters of Star Financial Group. Recently the city had lost almost 1,000 jobs due to the sale of Waterfield Mortgage Company.

A secure area at the Fort Wayne International Airport (formerly known as Baer Field) houses the Indiana Air National Guard's 122nd Fighter Wing, which flies the F-16 fighter.

While the homegrown Lincoln National Corporation has changed names and relocated its headquarters to Philadelphia, Lincoln Financial still employs about 1,500 professionals in the city and contributes millions of dollars annually to local charities and civic causes.

Publicly traded Steel Dynamics is headquartered in Fort Wayne. Privately held OmniSource, one of the nation's largest metallurgical recyclers, is also based in Fort Wayne.

United Art and Education, a mid-sized art supply retailer opened in the 1960s in Fort Wayne, has its headquarters located on Airport Expressway. It also has eight stores throughout the Midwest, with its highest selling store located in Fort Wayne.

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