On 21 October 1854, she and the staff of 38 women volunteer nurses including her head nurse Eliza Roberts and her aunt Mai Smith, and 15 Catholic nuns were sent to the Ottoman Empire. Nightingale arrived at Selimiye Barracks in Scutari early in November 1854. Her team found that poor care for wounded soldiers was being delivered by overworked medical staff in the face of official indifference. Medicines were in short supply, hygiene was being neglected, and mass infections were common, many of them fatal. There was no equipment to process food for the patients.

After Nightingale sent a plea to The Times for a government solution to the poor condition of the facilities, the British Government commissioned Isambard Kingdom Brunel to design a prefabricated hospital that could be built in England and shipped to the Dardanelles. The result was Renkioi Hospital, a civilian facility that, under the management of Edmund Alexander Parkes, had a death rate less than one tenth of that of Scutari.

Stephen Paget in the Dictionary of National Biography asserted that Nightingale reduced the death rate from 42% to 2%, either by making improvements in hygiene herself, or by calling for the Sanitary Commission. For example, Nightingale implemented handwashing and other hygiene practices in the war hospital in which she worked.