Luce was born in Tengchow (now Penglai), Shandong, China, on April 3, 1898, the son of Elizabeth Root Luce and Henry Winters Luce, who was a Presbyterian missionary. He received his education in various Chinese and English boarding schools, including the China Inland Mission Chefoo School.

Luce met his first wife, Lila Hotz, while he was studying at Yale in 1919. They married in 1923 and had two children, Peter Paul and Henry Luce III, before divorcing in 1935. In 1935 he married his second wife, Clare Boothe Luce, who had an 11-year-old daughter, Ann Clare Brokaw, whom he raised as his own. He died in Phoenix, Arizona in 1967. At his death, he was said to be worth $100 million in Time Inc. stock. Most of his fortune went to the Henry Luce Foundation, where his son Henry III served as chairman and chief executive for many years. During his life, Luce supported many philanthropies such as Save the Children Federation, the Metropolitan Museum of Art and United Service to China, Inc. He is interred at Mepkin Plantation in South Carolina.

At 15, he was sent to the US to attend the Hotchkiss School in Connecticut, where he edited the Hotchkiss Literary Monthly. There, he first met Briton Hadden, who would become a lifelong partner. At the time, Hadden served as editor-in-chief of the school newspaper, and Luce worked as an assistant managing editor. Both went on to Yale College, where Hadden served as chairman and Luce as managing editor of The Yale Daily News. Luce was also a member of Alpha Delta Phi and Skull and Bones. After being voted “most brilliant” of his class and graduating in 1920, he parted ways with Hadden to embark for a year on historical studies at Oxford University, followed by a stint as a cub reporter for the Chicago Daily News.

In December 1921, Luce rejoined Hadden to work at The Baltimore News. Recalling his relationship with Hadden, Luce later said, “Somehow, despite the greatest differences in temperaments and even in interests, we had to work together. We were an organization. At the center of our lives — our job, our function — at that point everything we had belonged to each other.”

Nightly discussions of the concept of a news magazine led Luce and Hadden, both age 23, to quit their jobs in 1922. Later that same year, they partnered with Robert Livingston Johnson and another Yale classmate to form Time Inc. Having raised $86,000 of a $100,000 goal, they published the first issue of Time on March 3, 1923. Luce served as business manager while Hadden was editor-in-chief. Luce and Hadden annually alternated year-to-year the titles of president and secretary-treasurer while Johnson served as vice president and advertising director. In 1925, Luce decided to move headquarters to Cleveland, while Hadden was on a trip to Europe. Cleveland was cheaper, and Luce’s first wife, Lila, wanted to leave New York. When Hadden returned, he was horrified and moved Time back to New York. Upon Hadden’s sudden death in 1929, Luce assumed Hadden’s position.

Luce launched the business magazine, Fortune, in February 1930 and acquired Life in order to relaunch it as a weekly magazine of photojournalism in November 1936; he went on to launch House & Home in 1952 and Sports Illustrated in 1954. He also produced The March of Time weekly newsreel. By the mid-1960s, Time Inc. was the largest and most prestigious magazine publisher in the world. (Dwight Macdonald, a Fortune staffer during the 1930s, referred to him as “Il Luce”, a play on the Italian Dictator Mussolini, who was called “Il Duce”.)

Once ambitious to become Secretary of State in a Republican administration, Luce penned a famous article in Life magazine in 1941, called “The American Century”, which defined the role of American foreign policy for the remainder of the 20th century (and perhaps beyond).

President Franklin D. Roosevelt, aware that most publishers were opposed to him, issued a decree in 1943 that blocked all publishers and media executives from visits to combat areas; he put General George Marshall in charge of enforcement. The main target was Luce, who had long opposed Roosevelt. Historian Alan Brinkley argued the move was “badly mistaken” and said had Luce been allowed to travel, he would have been an enthusiastic cheerleader for American forces around the globe. However, stranded in New York City, Luce’s frustration and anger expressed themselves in blatant partisanship.

Luce, supported by Editor-in-Chief T. S. Matthews, appointed Whittaker Chambers as acting Foreign News editor in 1944, despite the feuds that Chambers had with reporters in the field.

He was honored by the United States Postal Service with a 32¢ Great Americans series (1980–2000) postage stamp. Luce was inducted into the Junior Achievement U.S. Business Hall of Fame in 1977.