Stobhill was originally a Poor Law hospital, commissioned by the Glasgow Parish Council. The design competition, which was judged by John James Burnet, was won by Glasgow architects, Thomson & Sandilands. The foundation stone was laid in September 1901 by Lord Balfour of Burleigh, the then Secretary of State for Scotland, and Stobhill Hospital was formally opened on 15 September 1904, the same day as the Western District Hospital at Oakbank in Maryhill and the Eastern District Hospital at Duke Street. The original buildings are now graded as category B listed buildings.

It was built with 1,867 beds organised in eighteen two-storey red brick Nightingale ward blocks on a sprawling, 47-acre campus on the edge of Springburn Park. The Hamiltonhill Branch of the Lanarkshire and Dumbartonshire Railway, which ran past the northern boundary of the hospital grounds, facilitated the transport of coal and supplies to the hospital. The cost of the building was £250,000. It featured a large clocktower at the centre of the site, which has become a dominant landmark in the north of the city. The motto of the new hospital was Health is Wealth.

During the First World War, the building was requisitioned by the War Office to create the 3rd and 4th Scottish General Hospitals, facilities for the Royal Army Medical Corps to treat military casualties. Wounded servicemen arrived by specially converted hospital trains that terminated at a temporary railway platform built within the hospital grounds. A staff of 240 Territorial Force nurses as well as volunteers from the St. Andrew's Ambulance Association cared for over 1,000 patients at a time, suffering from battlefield wounds to venereal disease, until the return of the hospital to civilian use in early 1920.

In 1928 a new radiology department was opened and Stobhill became a general hospital in 1929. In 1930 Stobhill came under the control of the Glasgow Corporation and changed from being a Poor Law Hospital to become a Municipal Hospital due to the Local Government (Scotland) Act 1929. In 1931 a new maternity unit opened. In 1935, on the death of Sir Hugh Reid of the North British Locomotive Company in Springburn, he bequeathed the family's mansion at Balgrayhill, Belmont House, to the hospital in memory of his wife, and it was converted to become the Marion Reid Home for the care of babies and very young children in 1936. Stobhill became a teaching hospital in 1937 with the arrival of Noah Morris, Professor of Materia Medica at the University of Glasgow Medical School.