In April of 1849 he was elected to the office of Mayor for a one-year term. Two great catastrophies, fire and cholera, took place during his administration. Handling the resulting problems occupied most of his time as Mayor.

Fire broke out among steamboats at the levee on May 17, 1849. It burned 23 boats and the freight on the shore. The fire spread to the business district and destroyed most of it. The volunteer fire companies of that day were too weak to stop such a fire without great damage. Buildings were finally blasted with powder to provide a gap that halted the fire. The damage was estimated at $5,000,000. Mr. Barry approved several pieces of legislation as the result of the fire. $6,000 was appropriated immediately for relief of sufferers and for protection of property. No firewood was henceforth to be stored or sold at the wharf. The wood was to be inspected by the Lumber Master before being unloaded from the boat. Boats containing over 300 pounds of gun powder could not land within the City limits.

St. Louis was a city of about 64,000 population in 1849. During the early days of the cholera epidemic, deaths reached 639 per week. This came at a time of great immigration from Europe. Many died on the boats and others were very ill on arriving. Mayor Barry summoned a Citizens Committee that framed resolutions censuring the Council for its lack of leadership during the outbreak of the disease. Then the City Council met and appropriated $50,000 for the emergency, and transferred its authority to the Citizens Committee to fight the plague. Quarantine regulations were established. Passengers were examined aboard boat. The newspapers of this period praise Mayor Barry's handling of these two calamities, fire and cholera.