On August 21, 1971, Jackson met with attorney Stephen Bingham on a civil lawsuit Jackson had filed against the California Department of Corrections. After the meeting, Jackson was escorted by officer Urbano Rubiaco back to his cell when Rubiaco noticed a metallic object in Jackson's hair, later revealed to be a wig, and ordered him to remove it. Jackson then pulled a Spanish Astra 9 mm pistol from beneath the wig and said "Gentlemen, the dragon has come"—a reference to Ho Chi Minh.

It is not clear how Jackson obtained the gun. Bingham, who lived for 13 years as a fugitive before returning to the United States to face trial, was acquitted of charges that he smuggled a gun to Jackson.

Jackson ordered Rubiaco to open all the cells and along with several other inmates he overpowered the remaining correction officers and took them, along with two inmates, hostage. Five other hostages, officers Jere Graham, Frank DeLeon and Paul Krasnes, along with two white prisoners, were killed and found in Jackson's cell. Three other officers, Rubiaco, Kenneth McCray, and Charles Breckenridge, were also shot and stabbed, but survived.

After finding the keys for the Adjustment Center's exit, Jackson along with fellow inmate and close friend Johnny Spain escaped to the yard where Jackson was shot dead from a tower and Spain surrendered.

Three inmates were acquitted and three (David Johnson, Johnny Spain and Hugo Pinell) were convicted for the murders. The six became known as the "San Quentin Six".

There is some evidence that Jackson and his supporters on the outside had planned the escape for several weeks. Three days before the escape attempt, Jackson rewrote his will, leaving all royalties as well as control of his legal defense fund to the Black Panther Party.

Jackson's funeral was held at St. Augustine's Episcopal Church in Oakland, California on August 28, 1971.