Branham claimed that he had received an angelic visitation on May 7, 1946, commissioning his worldwide ministry and launching his campaigning career in mid-1946. His fame rapidly spread as crowds were drawn to his stories of angelic visitations and reports of miracles happening at his meetings. His ministry spawned many emulators and set the broader healing revival that later became the modern charismatic movement in motion. At the peak of his popularity in the 1950s, Branham was widely adored and "the neo-Pentecostal world believed Branham to be a prophet to their generation".[8] From 1955, Branham's campaigning and popularity began to decline as the Pentecostal churches began to withdraw their support from the healing campaigns for primarily financial reasons. By 1960, Branham transitioned into a teaching ministry.

Unlike his contemporaries, who followed doctrinal teachings which are known as the Full Gospel tradition, Branham developed an alternative theology which was primarily a mixture of Calvinist and Arminian doctrines, and had a heavy focus on dispensationalism and Branham's own unique eschatological views. While widely accepting the restoration doctrine he espoused during the healing revival, his divergent post-revival teachings were deemed increasingly controversial by his charismatic and Pentecostal contemporaries, who subsequently disavowed many of the doctrines as "revelatory madness".[9] His racial teachings on serpent seed and his belief that membership in a Christian denomination was connected to the mark of the beast alienated many of his former supporters. His closest followers, however, accepted his sermons as oral scripture and refer to his teachings as The Message. Despite Branham's objections, some followers of his teachings placed him at the center of a cult of personality during his final years. Branham claimed that he had converted over one million people during his career. His teachings continue to be promoted by the William Branham Evangelistic Association, which reported that about 2 million people received its material in 2018. Branham died following a car accident in 1965.

Throughout his healing revivals, Branham was accused of committing fraud by investigative news reporters, fellow ministers, host churches, and governmental agencies. Numerous people pronounced healed died shortly thereafter, investigators discovered evidence suggesting miracles may have been staged, and Branham was found to have significantly embellished and falsified numerous stories he presented to his audiences as fact. Branham faced legal problems as a result of his practices. The governments of South Africa and Norway intervened in order to stop his healing campaigns in their countries. In the United States, Branham was charged with tax evasion for failing to account for the donations received through his ministry; admitting his liability, he settled the case out of court. The news media has linked Branham to multiple notorious figures. Branham was baptized and ordained a minister by Roy Davis, the National Imperial Wizard (leader) of the Ku Klux Klan; the two men maintained a lifelong relationship. Branham helped launch and popularize the ministry of Jim Jones. Paul Schäfer, Robert Martin Gumbura, Leo Mercer, and other followers of William Branham's teachings have regularly been in the news due to the serious crimes which they committed. Followers of Branham's teachings in Colonia Dignidad were portrayed in the 2015 film Colonia.