Koresh was born Vernon Wayne Howell on August 17, 1959 in Houston, Texas, to a 14-year-old single mother, Bonnie Sue Clark (1944–2009) and father Bobby Wayne Howell (1939–2008). Before Koresh was born, his father met another teenage girl and abandoned Bonnie Sue. Koresh never met his father, and his mother began cohabiting with a violent alcoholic.

In 1963, Koresh's mother left her boyfriend and placed her 4-year-old son in the care of his maternal grandmother, Earline Clark. His mother returned when he was seven, after her marriage to a carpenter named Roy Haldeman. Haldeman and Clark had a son together named Roger, who was born in 1966.

In 1982, he moved to Waco, Texas, where he joined the Branch Davidians, not to be confused with the original Davidian Seventh-day Adventist group. A man named Ben Roden originated the Branch group. Roden had studied under Victor Houteff but upon the death of Houteff in 1955, he formed his own group with new teachings that were not connected with the original Davidians. Koresh played guitar and sang in church services at Mount Carmel Center. His band played a few times at clubs in Waco, and former members (such as David Thibodeau) have written that he recruited them through music. Koresh also tried to pursue his own record company but he was not successful due to lack of funds and support.

In 1983, Koresh began claiming the gift of prophecy. It is speculated by David Thibodeau in his 1999 book, A Place Called Waco, that he had a sexual relationship with Lois Roden, the prophetess and leader of the sect, who was then 65 years old, eventually claiming that God had chosen him to father a child with her, who would be the Chosen One. In 1983, Lois Roden allowed Koresh to begin teaching his own message, called "The Serpent's Root," which caused controversy in the group. Lois Roden's son George Roden intended to be the group's next leader and considered Koresh an interloper.

In 1985, Koresh and around 25 followers set up camp at Palestine, Texas, 90 miles (140 km) from Waco, where they lived under rough conditions in buses and tents for the next two years, during which time Koresh undertook recruitment of new followers in California, the United Kingdom, Israel and Australia. That same year Koresh traveled to Israel where he claimed he had a vision that he was the modern day Cyrus.

After being exiled to the Palestine camp, Koresh and his followers eked out a primitive existence. When Lois Roden died in 1986, the exiled Branch Davidians wondered if they would ever be able to return to Mount Carmel Center. But despite the displacement, "Koresh now enjoyed the loyalty of the majority of the [Branch Davidian] community". By late 1987, George Roden's support was in steep decline. To regain it, he challenged Koresh to a contest to raise the dead, going so far as to exhume a corpse to demonstrate his spiritual supremacy. Koresh went to authorities to file charges against Roden for illegally exhuming a corpse, but was told he would have to show proof (such as a photograph of the corpse).

In 1989, Roden murdered Wayman Dale Adair with an axe blow to the skull after Adair stated his belief that he (Adair) was the true messiah. Roden was convicted of murder and imprisoned in a psychiatric hospital at Big Spring, Texas. Since Roden owed thousands of dollars in unpaid taxes on Mount Carmel Center, Koresh and his followers were able to raise the money and reclaim the property.

Vernon Howell filed a petition in California State Superior Court in Pomona on May 15, 1990, to legally change his name "for publicity and Business purposes" to David Koresh. On August 28, 1990, Judge Robert Martinez granted the petition.

A six-month investigation of child abuse allegations by the Texas Child Protection Services in 1992 failed to turn up any evidence, possibly because the Branch Davidians concealed the spiritual marriage of Koresh to Michelle Jones, assigning a surrogate husband (David Thibodeau) to the girl for the sake of appearances.

The siege of Mount Carmel Center ended 51 days later on April 19, 1993, when U.S. Attorney General Janet Reno approved recommendations of FBI officials to proceed with a final advance in which the Branch Davidians were to be removed from their building by force. In an attempt to flush Koresh from the stronghold, the FBI resorted to pumping CS gas from a M728 Combat Engineer Vehicle with battering ram into the compound.

Koresh is buried at Memorial Park Cemetery, Tyler, Texas in the "Last Supper" section. Several of David Koresh's albums were released, including Voice Of Fire in 1994. In 2004, Koresh's 1968 Camaro, which had been damaged during the raid, sold for $37,000 at auction.

Timothy McVeigh and Terry Nichols cited The Mount Carmel Center raid as motivation for the Oklahoma City bombing of April 19, 1995—timed to coincide with the second anniversary of the Waco assault.

On January 23, 2009, Koresh's mother, Bonnie Clark Haldeman, was stabbed to death in Chandler, Texas; her sister, Beverly Clark, was charged with murder.

Koresh was one of the sources of inspiration used to create the fictional cult leader Joseph Seed in the 2018 action-adventure video game Far Cry 5.