When the Great Western Railway extended its main line from Reading through the Vale of White Horse in 1840 it opened the station as Faringdon Road station. After the Faringdon Railway between Uffington and Faringdon opened in 1864, the GWR renamed Faringdon Road "Challow" to avoid confusion.
The main station buildings and goods yard were on the up side of the line. A loading dock was provided. The line was originally double track. In 1932, the line was quadrupled between Challow and Wantage Road. The 1840-built timber station building on the up side was demolished, replaced by a new brick building. The 1873-built signal box on the down side of the line was also demolished and replaced by a new building. The down side platform was demolished and rebuilt to allow four tracks to run through the station, two fast straddled by two slow, designated Main and Relief. The station's platforms were on the slow lines, with the down platform having a "Pagoda" building, apparently for use as a waiting room. A loading dock was provided at the Uffington end of the down platform. In the goods yard, a grounded coach body served as a Methodist Church from the 1930s.
On 7 December 1964 British Railways withdrew passenger services from Challow and all other intermediate stations between Didcot and Swindon. The last passenger train ran on 5 December. The station closed to freight traffic on 29 March 1965. The signal box closed on 30 May 1965. The goods shed was demolished the next month.
Few parts of the station survive. The northern platform has almost disappeared completely and the southern platform is used by Network Rail, although no buildings remain and the buildings used by Network Rail are only small portable cabins, including a relay room. New buildings have been built around the site. The most noticeable is the bail depot on the site of the northern platform. One nearby public house, the Prince of Wales, was burnt down in 1999 and the site has been levelled.