Motorists will face more delays on the Heads of the Valleys road, with an £800m upgrade causing further closures.
The road was closed in Merthyr Tydfil between Dowlais Top and Cefn Coed from Wednesday until Friday morning after a lorry carrying tyres burst into flames.
It shut at 20:30 BST on Friday between Brynmawr, Blaenau Gwent and Gilwern, Monmouthshire.
A 27-mile (44km) diversion will be in place until 06:00 on Monday.
Contractors will install a footbridge and do work to the Gateway Arch Bridge on the five-mile stretch of the A465 over the weekend.
This latest phase of the works will cost about £220m and is due to be completed in late 2019, is part of a 20-year project to dual the route between Swansea and the Midlands.
The diversion will go through Pontypool and Crumlin on the A467, A472 and A4042 roads.
Ministers described the route as "a crucial artery of our transport network and the principal road link between west Wales and the Midlands".
The upgrade work involves widening the existing road which passes through Clydach Gorge, which is considered one of south Wales' most important environmental and ecologically sensitive areas.