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The station was opened on 30 May 1846 by the South Devon Railway. The company had joint use of the Bristol and Exeter Railway station at St David's but St Thomas was its own station. Although built on a 501 yards (458 m) stone viaduct (see - St. Thomas Viaduct, Exeter) - , the railway was nearer to the city centre and the quays on the Exeter Canal. Until 1862 tickets were only sold between St Thomas and stations west of Exeter, not to St David's and the north.
The railway was worked by atmospheric trains from 13 September 1847 until 9 September 1848. Unique in all the South Devon Railway stations, there was no engine house, so the driver had to hold the train on its brakes against the pressure in the pipes while it was stopped here.
The original station featured just a single track with a 175 feet (53 m) platform on the city side of the line. A small booking office was built at road level at the north end of the station and steps led up to the platform. The viaduct was widened at this point by five feet to accommodate the platform.
In 1847 some improvements were completed including a larger office, a train shed over the platform, and an extension to bring the platform to a length of 260 feet.
In 1851 George Hennet was given permission to build a coal depot at St Thomas from where he could distribute coal, brought by train from his quay at Teignmouth. The site is now occupied by the Great Western Railway Staff Association staff club.
In 1861 the viaduct was widened on the west side (away from the city), and a second track brought into use which necessitated a second platform be built. New two-storey buildings were built on the city side of the viaduct, and a new train shed built across both platforms.