Jackrabbit Jewel and Conejo Grande find themselves immersed in a new adventure along the Butterfield Overland Mail route. This mail route covered a distance of 2,800 miles, beginning in St. Louis, Missouri, and ending in San Francisco, California. As in the previous adventure of Jackrabbit Jewel in Jackrabbit Jewel and the Longhorn Cattle Drive, this story blends the history of the southwestern United States with Texas Tall Tale.

The president of the Overland Mail Company, John Butterfield, sends Jackrabbit Jewel an urgent message. Due to a lack of stagecoach drivers, he needs Jewel to drive the stagecoach from Fort Smith, Arkansas, to San Francisco. In addition, he needs Conejo Grande to pull the stagecoach. In addition to the bundles of U.S. mail, they are transporting three passengers to California. The trip is fraught with danger during every stage of their journey, but Jewel has keen frontier knowledge and the help of Conejo Grande and her passengers.