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Business career, 1898–1920

By the late 1890s, Mellon had amassed a substantial fortune, but his wealth paled in comparison to that of better-known business leaders such as John D. Rockefeller. In the late 1890s, the Union Trust Company emerged for the first time as one of Mellon's most important and profitable holdings after Mellon broadened the company's activities to include commercial banking. With an infusion of capital from Union Trust, Mellon underwrote the capitalization of National Glass and several other companies. He also became a co-owner of the McClintic-Marshall Construction Company and established Crucible Steel Company, the Pittsburgh Coal Company, and the Monongahela River Coal Company; the two coal companies collectively contributed 11 percent of the coal production of the United States. With Frick, Richard Mellon, and William Donner, Mellon co-founded Union Steel Company, which specialized in the production of nails and barbed wire. Though Frick had fallen out with steel magnate and long-time business partner Andrew Carnegie, Mellon received Carnegie's consent to venture into the steel industry. Responding to the growing emphasis on naval power in the aftermath of the Spanish–American War, Mellon and Frick also became major shareholders in the New York Shipbuilding Corporation.

In 1902, Mellon reorganized T. Mellon & Sons as the Mellon National Bank, a federally chartered National Bank. Andrew Mellon, Richard Mellon, and Frick drew up a new business arrangement in which the three of them jointly controlled the Union Trust Company, which in turn controlled Mellon National Bank. They also established Union Savings Bank, which accepted deposits by mail, and the Mellon banks flourished in the first years of the 20th century. While Mellon's financial empire prospered, his investments in other areas, including Pittsburgh's streetcar network, the Union Steel Company (which was bought out by U.S. Steel), and the Carborundum Company, also paid off handsomely. Another successful Mellon investment, the Standard Steel Car Company, was created in partnership with three former U.S. Steel executives. As part of the Texas oil boom, the Mellons also helped J. M. Guffey establish the Guffey Company. The Mellons later removed Guffey as the head of his company, and in 1907 they reorganized the Guffey Company as Gulf Oil and installed William Larimer Mellon Sr. (a son of Andrew Mellon's older brother, James Ross Mellon) as the head of Gulf Oil. The success of Mellon's financial empire and his varied investments made him, according to biographer David Cannadine, the "single most significant individual in the economic life and progress of western Pennsylvania" in the first decade of the 20th century.

The Panic of 1907 devastated several companies based in Pittsburgh, ending a period of strong growth. Some of Mellon's investments experienced a sustained down period after 1907, but most experienced a quick recovery. Mellon also became an investor in George Westinghouse 's Westinghouse Electric Corporation after he helped prevent the company from going into bankruptcy. By the end of 1913, Mellon National Bank held more money in deposits than any other bank in Pittsburgh, and the Farmer's Deposit National Bank, which held the second-largest amount of deposits, was controlled by Mellon's Union Trust Company. In 1914, Mellon became a co-owner of Koppers, which produced a more sophisticated coking oven than the one that had earlier been pioneered by Frick. He also served as a director of various other companies, including the Pennsylvania Railroad and the American Locomotive Company. Mellon was deeply involved in the financing of World War I, as the Union Trust Company and other Mellon institutions provided millions of dollars in loans to the United Kingdom and France, and Mellon himself invested in Liberty bonds.