In 1878 on the advice of his physician, Flagler traveled to Jacksonville, Florida for the winter with his first wife Mary, who was quite ill. Two years after her death in 1881 he remarried.  Her name was Ida Alice Shrouds. She had been a nurse to his first wife. After their wedding, the couple traveled to Saint Augustine, Florida. Flagler found the city charming, but the hotel facilities and transportation systems inadequate. He immediately recognized Florida's potential. He returned to Saint Augustine in 1885 and began construction on the 540-room Ponce de Leon Hotel. Now all that was needed was a sound transportation system to support his hotel ventures, Flagler purchased his first railroad. It would later be renamed the Florida East coast Railway.

In 1897 Ida Alice was committed to an insane asylum in New York. Insanity wasn't grounds for divorce in either New York or Florida. Flagler convinced the Florida legislature to change its law in 1901. He then married Mary Lily Kenan, whom he had known for about eight years.

Flagler went on to complete the 1,100-room Royal Ponciana Hotel on the shores of Lake Worth in Palm Beach. Two years later, Flagler built the Palm Beach Inn (renamed The Breakers Hotel in 1901) This mammoth structure overlooked the Atlantic Ocean in Palm Beach. By 1905, Flagler decided that his Railway should extend from Biscayne Bay to Key West. At the time, Key West was Florida's most populous city and the United States' closest water port to the canal that the U.S. government proposed to build in Panama. Flagler wished to take advantage of additional trade with Cuba and Latin America, not withstanding the increased trade that the Panama Canal would bring. In 1912, the Florida Over-Sea Railroad was completed to Key West.

 In 1913, Flagler fell down a fight of stairs at Whitehall (his home). He never recovered and died in Palm Beach of his injuries on May 20th at 83 years of age. He is buried in Saint Augustine alongside his daughter and first wife Mary. Only his son Harry survived of the three children by his first marriage. There is a monument to him on Flagler Island in Biscayne Bay. Flagler College is named after him in Saint Augustine. Whitehall, Palm Beach, is open to the public as the Henry Morrison Flagler Museum; his private railcar No.91 is preserved inside a Beaux Arts pavillion built to look like a 19th Century railway palace.