Son of a poor minister, Flagler left school at 14 to become a merchant in Ohio. Through grain and distillery business, he met John D. Rockefeller, in Bellevue, Ohio. After a business disaster as a salt manufacturer in Saginaw, Michigan, he moved to Cleveland and soon joined Rockefeller in what was to become Standard Oil. Second only to Rockefeller, he retained his business interest in Standard Oil until the end of his life. In 1883 he visited Florida. He initially centered his work on developing St. Augustine, Florida, but when a rare freeze struck that city, he decided to run his railroad further south along the peninsula.
He developed the Flagler Railroad eventually spanning from Daytona to Key West with associated luxury hotels there. This lead to the development of Miami which was only a hamlet. Flagler encouraged fruit farming and settlement along his railway line and made many gifts to build hospitals, churches and schools in Florida.
Only his son Harry survived of the three children by his first marriage in 1853 to Mary Harkness. His second marriage in 1883 to Ida Shourds ended in divorce due to her insanity. In 1901 he married Mary Kenan.
There is a monument to him in Biscayne Bay, and a University named after him in St. Augustine, Florida.