The pair, who summoned a quirky chemistry in 1998's The Wedding Singer and 2004's 50 First Dates, will star in Blended, due for release on Memorial Day 2014.
Barrymore and Sandler will play mismatched single parents who independently arrive at the same luxury resort in Africa with their families.
The film also stars Joel McHale (of Community and The Soup), Wendi McLendon-Covey (Bridesmaids and Reno 911), Kevin Nealon (Weeds) and Terry Crews (Brooklyn Nine-Nine).
The movie also reunites its leading man with director Frank Coraci, a veteran of Sandler's The Wedding Singer, The Waterboy and Click.
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