The first station to open in the Paddington area was a temporary terminus for the Great Western Railway on the west side of Bishop's Bridge Road. The first GWR service from London to Taplow, near Maidenhead, began at Paddington in 1838. After the opening of the main station in 1854, this became the site of the goods depot. After years of dereliction, it is now being redeveloped as part of a mixed residential and business area called Paddington Waterside.

The main Paddington station between Bishops Bridge Road and Praed Street was designed by Isambard Kingdom Brunel, although much of the architectural detailing was by his associate, Matthew Digby Wyatt. It was opened in 1854.

The glazed roof is supported by wrought iron arches in three spans, respectively spanning 20.7 m (68 ft), 31.2 m (102 ft) and 21.3 m (70 ft). The roof is 213 m (699 ft) long, and a particular feature of the original roof spans is the presence of two transepts connecting the three spans. It is commonly believed that these were provided by Brunel to accommodate traversers to carry coaches between the tracks within the station. However, recent research, using early documents and photographs, does not seem to support this belief, and their actual purpose is unknown.

The Great Western Hotel was built on Praed Street in front of the station in 1851-1854 by architect Philip Charles Hardwick, son of Philip Hardwick who designed the Euston Arch. The station was substantially enlarged between 1906 and 1915 and a fourth span of 33 m (109 ft) was added on the north side, parallel to the others. The new span was built to a similar style to the original three spans, but the detailing is different and it does not possess the transepts of the earlier spans.

A very early construction by Brunel was recently discovered immediately to the north of the station. A cast iron bridge carrying the Bishop's Bridge Road over the Paddington Arm of the Grand Union Canal was uncovered after removal of more recent brick cladding during the complete replacement of the adjacent bridge over the railway lines at the mouth of the station.

Paddington station is served by four London Underground lines through two separate stations. The Bakerloo, Circle and District lines serve a combined sub-surface and deep-level station to the south of the main line station; and the Hammersmith & City and Circle lines serve a sub-surface station to the north. Circle line services are routed through each of the sub-surface stations as part of a spiral route. Although shown on the London Underground map as a single station, the two sub-surface elements are not directly linked.