Her medical complement included nurses from the Catholic order Sisters of the Holy Cross, the first volunteer females to serve on board a Navy ship.

In addition to caring for and transporting sick and wounded men, she provided medical supplies to Navy ships along the Western Rivers.

At the time of Red Rover's commissioning as a hospital ship, the Union was already using steamers such as the City of Memphis as medical transports to carry casualties upriver.

Barges, housed over or covered with canvas, were ordered for the care of contagious diseases, primarily smallpox, and were moored in shady spots along the river.

Rapid mobilization at the start of the Civil War had vitiated efforts to prevent the outbreak and epidemic communication of disease on both sides of the conflict.

Her conversion to a hospital boat, begun at St. Louis, Missouri, and completed at Cairo, Illinois, was undertaken by the Western Sanitary Commission with both sanitation and comfort in mind.

An elevator, numerous bathrooms, nine water closets, and gauze window blinds " ... to keep cinders and smoke from annoying the sick" were also included in the work.

Red Rover, dispatched to assist in the emergency, took on board extreme burn and wound cases at Memphis, Tennessee, and transported them to less crowded hospitals in Illinois.

Through the summer, she treated the flotilla's sick and wounded while the Ram Fleet engaged at Vicksburg and along the Mississippi River to Helena, Arkansas.

The next day, the Union transferred the vessels of the Western Flotilla, with their officers and men, to the Navy Department to serve as the Mississippi Squadron under acting Rear Adm. David Dixon Porter.

The Red Rover also hosted 5 African-American former slaves who were enlisted as "Boys" and were paid to serve as Nurses in the Navy, and these women: Ann Bradford Stokes, Ellen Campbell, Alice Kennedy, Sarah Kinno and Betsy Young (later became Young Fowler) were the forerunners and pre-dated the formation of the Navy Nurse Corps.

From February to the fall of Vicksburg early in July, she cared for the sick and wounded of that campaign and supplemented her medical support of Union forces by provisioning other ships of the Mississippi Squadron with ice and fresh meat.

After delivering medical stores to ships at Helena and on the White, Red, and Yazoo Rivers, she transferred patients to Hospital Pinckney at Memphis and headed north.