The second of two old bridges is being demolished after new, wider replacements were installed last year.
The M6 under Junction 10 was closed at 8pm on Friday and will remain shut until around 5am on Monday. Motorway traffic is being be diverted up and over at the roundabout, while people in the area have been asked to take alternative routes if possible or allow extra time for journeys.
The long-term project aims to reduce congestion at the historic bottleneck junction in Walsall where the motorway meets the A454 Wolverhampton Road/Black Country Route.
The south bridge was demolished earlier this month and the remaining north bridge is now being removed. When the work is completed the number of lanes over the motorway will double from two to four.
An "up and over" diversion for traffic is again in place, with drivers leaving the motorway at Junction 10, travelling over the roundabout and then rejoining the M6 on the other side. The Junction 9 northbound entry slip road will also be shut to reduce congestion on the approach to the junction 10 closure.
National Highways has said it is expecting severe delays during the closure.
Elsewhere in the region further congestion was expected in Smethwick and Birmingham, with the Sandwell Aquatics Centre hosting a test event this weekend ahead of the summer's Commonwealth Games, and the Müller Birmingham Diamond League taking place at Alexander Stadium on Saturday, coinciding with highways works in Perry Barr.