The retailer has teamed up with motorway services operator Welcome Break to open 2,500 sq ft food stores next month at Oxford Services on the M40 and South Mimms on the M25.
More than 850 on-the-go and convenience lines, including sandwiches, salads, drinks, bread, milk and ready meals, will be available in the stores, which will be run by Waitrose staff and open seven days a week from 7am to 10pm.
The retailer hoped to broaden its customer base by becoming more accessible to motorists, said Waitrose commercial director Richard Hodgson.
"M&S Simply Food has worked, to my knowledge, so I don't see why ours would not. It's about giving people more opportunities to buy the best-quality food and drink. There are 24 Welcome Breaks so if these are a success, there is potential to open more."
The move builds on Waitrose's ventures into new smaller store formats such as Market Town and Convenience.
While the motorway stores will be less than half the size of the retailer's recently launched c-stores in Nottingham and Bristol, there will be overlaps between the two formats, said Hodgson.
"The stores will provide food and drink for immediate consumption. We will also sell ready meals as lots of people will shop on their way home. We are likely to discover new things suitable for our c-store offer."
Hodgson added that Waitrose would consider working with other parties on business opportunities if they shared its values.