St. Louis was affected by the cholera epidemic of 1832-1833 that spread across America from Europe with several hundred people dying. Subsequent visitations were less virulent, killing mostly children, the elderly, and the sick. By the year 1849 Saint Louis had become a boomtown with a rush of gold seekers heading to California. At the same time a large numbers of German immigrant, refugees of the recent revolution in that country, began arriving in St. Louis. It is believed that these immigrants carried the disease from their homeland to New Orleans and then upriver to St. Louis. Early in 1849, St. Louis reported the beginnings of the plague with conditions reaching an epidemic in May. The epidemic reached its peak in July, when 145 persons died in one grisly day and 722 in one week. By the end of that month over 4,500 cholera victims had been buried in the city since the first of the year, or over ten percent of the city's population.

Because of the large number of deaths most of the city's cemeteries, including all of its Catholic cemeteries, had been filled to capacity due to the epidemic. Following the outbreak the city passed an ordinance that required all new cemeteries to be located beyond the city limits hoping that this measure might prevent another epidemic. In 1853, Archbishop Peter Richard Kenrick purchased the 323-acre "Old Orchard Farm" northwest of the city from Kentucky politician Henry Clay. Kenrick established his own farm on half of this acreage and dedicated the other half to the development of a new cemetery. As the cemetery grew, more acreage was added to its site. Part of this property had once been used as an ancient burial ground by Native Americans and soldiers from nearby Fort Bellefontaine were also interred there. After its purchase, these remains were collected and buried in a mass grave under a large crucifix. It is located at one of the highest points of the cemetery. Graves from many of the Catholic cemeteries in the city were reinterred in Calvary. The cemetery now contains over 315,000 graves in its 477 acres and is one of St. Louis’ largest cemeteries. The graves of many noteworthy St. Louisans, including Civil War General William Tecumseh Sherman; Dred Scott, the slave who gained a place in American history when he sued for his freedom, and playwright Tennessee Williams, are here. The cemetery also contains many architecturally significant tombs and memorials. A tour guide listing the gravesites can be picked up at the office.