The A487 in Powys will shut for six nights for resurfacing works, leading to long diversions around Machynlleth.
It will close at points between the Ceredigion-Powys border and Machynlleth railway station from 19:30 BST to 06:00 each night, from Monday to Friday and again on 9 March.
The road will be open from 10 to 13 March, but with restrictions.
The Welsh Government said there were "no suitable alternatives" to the "lengthy diversions" it will cause.
The closure means the journey from Machynlleth to Aberystwyth, for instance, which is usually about 18 miles (28km), will be 60 miles (96km), via diversions through Caersws and Llangurig.
Posting about the closures on Facebook, town clerk Jim Griffiths apologised for the "disruption and disturbance" caused at "very short notice".
He said residents and businesses needing direct access on the sections of roads affected would be accommodated but there would be delays, and he advised people to avoid the roads during the closures.
"I am aware that there will be impacts that are felt more by some than others, but again can only apologise and assure you that everyone involved will be doing their best to keep things running as best we can," he said.
As well as the disruption to the A487, there will also be night closures on the A489 at the Dolguog junction on 16 and 17 March.
Heulwen Davies, who lives in Derwenlas, where the road is closed, said: "I understand the need to work on the roads but the lack of communication with the locals is appalling.
"Other than Facebook I knew nothing about it and I live in the village which is cut off in both directions.
"They seem to treat us as inferior residents, this would not happen in our big towns and cities."
A Welsh Government spokesperson said: "We appreciate this is a lengthy diversion but there are no suitable alternatives on the road network when a closure is necessary.
"The timeframe has been chosen for reasons including contractor availability and programmes of works on other roads. We have tried to minimise disruption, though the nature of the work makes some unavoidable.
"We are grateful to local businesses and residents for their patience."