The discoveries near Hamilton in South Lanarkshire include coins believed to date from the 10th or 11th century, and fragments of glazed medieval pottery and clay smoking pipes.
They were found under the motorway verge near junction six, opposite the Hamilton Services.
It came during work to widen that stretch of the M74 as part of the £500 million improvements to the motorway and nearby M73 and M8 by Transport Scotland.
The Scottish Government agency said archaeologists believed this could finally identify the location of the lost village of Cadzow - now part of Hamilton.
James II gave permission for Cadzow to be renamed Hamilton in 1445, after the Dukes of Hamilton, who owned lands in the area.
Archeologists said the site may have lain undisturbed because it was where the Netherton Cross, which also dates from 10th or 11th century, once stood,
A memorial stone was left to mark the spot when the cross was moved to Hamilton Old Parish Church in 1925.
They said that although the area was heavily mined during the 19th century, the area around the cross may have been left for religious reasons.
Road workers in the 1960s may have been similarly unwilling to disturb it.
Last year, coins which were then believed to be from the reign of Charles I in the mid-17th century were found nearby after a medieval structure was uncovered adjacent to the motorway.
Lead archaeologist Warren Baillie said he was “really surprised” the ruins had survived the extensive work involved in constructing that section of the M74 in the 1960s.
Kenny Green, one of four archaeologists nicknamed ‘The Time Detectives’, was scraping away at a gap between two stones when he spotted the coin.
Mr Baillie, project manager for Guard Archaeology, said last autumn: “This is a very interesting find.
“We have been on site for 18 months now and this is the most significant discovery to date.
“No-one thought anything like this could have survived.
“We are delighted to have been there to recover a piece of Scottish history.”
Infrastructure secretary Keith Brown is due to visit the site to view the finds on Thursday.