On 2 September 1925 USS Shenandoah left her base at Lakehurst, New Jersey, to begin a flight to the Midwest. This voyage was one of a series of publicity trips by the Navy's airships that were intended to enhance public support for Naval Aviation, but which also kept the dirigibles away from the Fleet and reduced opportunities to serve with the operating forces. Shenandoah's journey was planned to take her to an air show at St. Louis, Missouri, then north to Minneapolis, Minnesota, and return by way of Dearborn, Michigan.

During the early morning darkness of 3 September, Shenandoah was flying over southeastern Ohio when she abruptly encountered violent atmospheric conditions. Powerful air currents buffeted her so severely that her crew was unable to maintain control. Rising rapidly above her pressure height, then falling and rising again, her hull structure was overstressed amidships, breaking the airship in two. Shenandoah's external control car and two engine cars fell free, carrying the dirigible's Commanding Officer, Lieutenant Commander Zachary Lansdowne, and several other men to their deaths. The stern section came down nearby, while Lieutenant Commander Charles E. Rosendahl and several men were able to fly the bow section to ground as a free balloon. In all, twenty-nine of those on board survived.

Shenandoah's crash was the nation's most dramatic aviation disaster yet. Fourteen trained crewmen had been killed and a valuable Navy asset had been lost. Criticism, both public and professional, was intense. Though the remaining dirigible, USS Los Angeles (ZR-3), operated safely for several more years, and new airships were designed to be much stronger than Shenandoah, her mid-air breakup had forcefully demonstrated the threat that weather presented to lighter-than-air craft. Less than a decade later, storms would cause the loss of the new, much larger and more capable airships Akron (ZRS-4) and Macon (ZRS-5), bringing an end to the Navy's brief experiment with rigid airships.