The Department for Culture, Media and Sport has approved 35 new listings and upgraded status for seven structures along the railway line, designed by Victorian engineer Isambard Kingdom Brunel.
The route, which runs from London Paddington to Temple Meads in Bristol, was built in 1836 to open up new trade links between the cities.
Among the safeguarded structures is the now grade II listed Wiltshire box tunnel, which English Heritage says is one of the most extensive and famous of the pioneering Great Western Tunnels.
Other listings include the Roman Road Bridge in Swindon and the River Avon Viaduct, both also given grade II status.
Structures being upgraded to Grade II*, include the Sydney Gardens Footbridge in Bath, which was built in 1841 and is the last surviving example of Brunel’s cast-iron bridges on the Great Western route, and Moulsford Viaduct in South Oxfordshire.
Maidenhead Railway Bridge in Buckinghamshire, which is believed to have the longest and flattest brick arches ever built, has been upgraded to Grade I listing.
Heritage minister John Penrose said: "Our railways and the historic buildings that go along with them are a wonderful and emotive part of our national heritage, symbolising for many of us a sense of romance, history and adventure. I am very pleased to be able to give these buildings, bridges and tunnels the extra protection that listing provides."
English Heritage head of designation Emily Gee said the scale of consultation it conducted on the designations was unusual for the national heritage advisor and it was pleased with the "thoughtful responses" received from railway history experts, local authorities and other heritage bodies.
She added: "I am also impressed by Network Rail’s commitment to respecting the special structures in their care. We certainly hope to do more of this kind of partnership working with protection outcomes under our National Heritage Protection Plan."