The bridge will shut to all traffic from 7pm on Friday (July 1) until 6am on Monday (July 4).
Diversions will be in place via the Prince of Wales Bridge.
National Highways says the ongoing maintenance work - which involves checking the two main suspension cables for signs of corrosion - is essential to keep the bridge "in a safe and serviceable condition."
Chris Pope, Project Manager for National Highways, said: “Built over 55 years ago, the M48 is a crucial route across the River Severn and it is imperative we maintain it long into the future.
“The inspections are vital to allow us to understand the current condition of the suspension cables and confirm that the measures that we implemented over the last 15 years have been effective in ensuring the long-term viability of the bridge and the safety of its users.
“We understand this work may cause some inconvenience and disruption, but we will make every effort to ensure the impact on drivers is kept to a minimum.
“We are working in conjunction with the Welsh Government and its South Wales Trunk Road Agency to ensure minimum disruption during the closures, and avoiding any major events on either side of the bridge.”