In 1865, Rockefeller took out a loan to purchase out some of his partners and acquire control of Cleveland's largest refinery. Over the next five years, he added partners and grew his oil industry business. During the time, kerosene, a petroleum product used in lights, was a staple. Rockefeller founded the Standard Oil Company of Ohio in 1870 with his younger brother William (1841-1922), Henry Flagler (1830-1913), and others. John Rockefeller was its president and biggest stakeholder. Standard Oil bought competing refineries and created global distribution and marketing organizations to monopolize the oil industry. The Standard Oil Trust, formed in 1882, controlled 90% of the nation's refineries and pipelines. Standard Oil built its own oil barrels and hired scientists to find new uses for petroleum byproducts to exploit economies of scale. Muckraking journalists, reform politicians, and others saw Rockefeller as a symbol of corporate greed and condemned his actions. In 1937, The New York Times reported: “He was accused of crushing out competition, getting rich on rebates from railroads, bribing men to spy on competing companies, making secret agreements, coercing rivals to join the Standard Oil Company under threat of being forced out of business, building up enormous fortunes on the ruins of other men, and so on.”

In the mid-1890s, Rockefeller retired from running Standard Oil. Rockefeller donated more than half a billion dollars to educational, religious, and scientific causes through the Rockefeller Foundation, inspired in part by fellow Gilded Era mogul Andrew Carnegie (1835-1919), who created a fortune in the steel industry and then gave it away. He founded the University of Chicago and Rockefeller Institute for Medical Research (now Rockefeller University). Rockefeller was a fervent Christian, temperance activist, and golfer. He died at 97 at The Casements in Ormond Beach, Florida, on May 23, 1937. (Rockefeller possessed a mansion in New York City, an estate in Lakewood, New Jersey, and Kykuit, Dutch for "lookout," on 3,000 acres near Tarrytown, New York.) Cleveland Lake View Cemetery buried him.