The Belgian carrier will operate 12 flights a week to the country’s capital.
Flights will be operated by wet-lease partner CityJet starting 1 September.
The route, previously operated by Flybmi, was pulled when the regional carrier ceased operations in February.
Between 1 September and 27 October, Brussels Airlines will operate the route six times a week before increasing frequency to 12 weekly flights thereafter.
Bristol is the airline’s fifth UK departure, its network already including Birmingham, Edinburgh, London and Manchester.
Andreas Koester, Brussels Airlines senior sales director UK, Ireland and Iceland Lufthansa Group, said the new connection was an “important expansion” of parent Lufthansa’s UK network.
“With two flights daily out of Bristol, Brussels Airlines offers point-to-point passengers a flexible schedule and create a broad range of possibilities for passengers connecting to one of the many other destinations in our network.”
Nigel Scott, Bristol airport business development director, added the route would offer “extensive onward connectivity options” for passengers.
“The service will appeal to passengers travelling for business or leisure,” said Scott. “It offers opportunities for inbound visitors using Bristol as a gateway to the region.
"With frequent travel connections, inbound tourists will be able to experience the vibrant cities of Bristol and Bath, and the host of iconic tourist attractions and beautiful coastline we have in the region.”
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