The northbound carriageway will be fully closed between junctions 6 (Bickenhill Interchange) and 8 (Coleshill). Both link roads from the M6 to the M42 will also be closed at the same times.
The southbound carriageway will remain open during the day but will be shut overnight between junctions 9 (Dunton Interchange) and 6 (Bickenhill).
In December, the world's largest 'box slide' was installed, acting as a 2,600-tonne bridge over the M42 to reduce the amount of disruption caused by the project.
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During June's overnight works, HS2's main contractor for the West Midlands, Balfour Beatty VINCI (BBV), will install parapets, safety barriers and monitoring equipment on the Marston Box bridge.
Commenting on the disruption, National Highways Senior Planner, Frank Bird said: "On Saturday and Sunday we'll have Traffic Officers patrolling the M42 on the approach to the closures as well as the diversion routes to help clear any incidents quickly and keep traffic flowing.
"West Midlands Police motorbikes will provide additional support during the day by ensuring motorists don't block the yellow box on the M42 at junction 6 and they'll also periodically check the diversion route. We'll have free recovery in place on the diversion as well.
"We advise people to plan their journeys in advance, familiarise themselves with the diversions and allow extra time for their journeys."
Reflecting on the use of the 'box slide' Sasan Ghavami, BBV's Construction Director for the project, said: "The box-slide we completed over Christmas allowed us to move the bridge structure in one movement, reducing our impact on the road network overall.
"Our work this month is a highly important step that will allow us to safely deliver the UK’s new high speed rail line."
