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Sprinkel served as executive vice president and economist for the Harris Trust and Savings bank in Chicago. He was also director of the economic and financial forecasting service, which published Harris Economics. During his 28 years at Harris, he served as a consultant to various government agencies and congressional committees.

From 1948 to 1952, Sprinkel taught economics and finance at the University of Missouri School of Business and Public Administration and the University of Chicago Booth School of Business. For 20 years he served as one of the three economic forecasters at Chicago Booth's annual Business Forecast Luncheon. In addition to writing numerous articles and two books, he coauthored a third that discusses effects of monetary policy on financial markets and the economy.

In 1985, President Ronald Reagan appointed Sprinkel chairman of the U.S. Council of Economic Advisors. Previously, he had served for four years as undersecretary of the Treasury for monetary affairs, brining to government the experience and perspective of an economist who had a long and distinguished career in business and academia.

Sprinkel has been a member of Time magazine's board of economists, chairman of the Economic Advisory Committee of the American Bankers Association, a member of the board of directors of the U.S. Chamber of Commerce, and a founding member of the Shadow Open Market Committee. A chartered financial analyst, he received honorary degrees from DePaul University and St. Michael's College.