Though appearing to be the remnant of a volcanic neck, it is now believed to be a tilted and eroded piece of rock overlain by a lava flow.

In 1775 the peak was referred to as Cerro de Taca 'Taca Hill' by Father Francisco Garcés, using the Oʼodham name Tcacca or Taceo.

The park is near the site of the Battle of Picacho Pass, one of several American Civil War era engagements to occur in Arizona Territory.

Picacho Peak features prominently in the novel The Host by Stephenie Meyer, serving as a guide to the main character in the first act of the story.

On June 8, 2024, a plane crashed near the summit of Picacho Peak, killing its pilot, 68-year-old James Galvin of Oro Valley.