Orozco was born to a lower-middle class family on a hacienda in the state of Guerrero. He worked as a muleteer and store keeper, before he became rich from an investment in a gold mine.
He objected to the Porfirio Díaz dictatorship, first getting into trouble with the law when caught with anti-Díaz literature in 1906. When Francisco I. Madero called for revolt against Díaz in 1910 Orozco was an enthusiastic supporter, and on 31 October of that year was placed in command of the revolutionary forces in Guerrero. He led his forces to a series of victories against Díaz loyalists, and by the end of the year most of the state was in rebel hands. Madero promoted him to colonel, and in early 1911 to brigadier general. On 10 May of that year Orozco and Pancho Villa sized Ciudad Juárez, which Madero made the capital of his provisional government.
After Díaz's fall, Orozco became resentful at Madero's failure to name him to the cabinet or state governorship. When Madero asked him to lead troops against the forces of Emiliano Zapata, and Orozco refused and offered his resignation, which Madero did not accept. Orozco was then offered governorship of Chihuahua State, which he refused, and Madero finally accepted his resignation from the Federal government.
On 3 March, 1912 Orozco decreed a formal revolt against Madero's government. Madero sent general Victoriano Huerta to stop Orozco's rebellion, which by August Huerta had done. Orozco took refuge in the United States.
After Huerta installed himself as President of Mexico, Orozco agreed to support him if Huerta agreed to some reforms (such as payment of hacienda workers in hard money rather than company store scrip). Huerta agreed, and had Orozco lead forces against Pancho Villa.
After Huerta's fall Orozco announced his refusal to recognize the government of new president Francisco S. Carbajal. After briefly leading a revolt in Guanajuato he was again forced into exile in the United States.
In the US he met with Huerta to make plans to retake Mexico. On 27 June, 1915 the two were arrested in Newman, New Mexico, and charged with conspiracy to violate U.S. neutrality laws. He was placed under house arrest in El Paso, Texas, but managed to escape back into Mexico.
He led a small guerilla band in northern Mexico, making occasional raids across the US border. After raiding a ranch his band was pursued by Texas Rangers. Orozco was shot and killed; it was not until afterwards that his pursuers discovered he was anything other than a common bandit.
On 3 September, 1915 Orozco's remains were buried in El Paso. The remains were moved to Chihuaha in 1923.