Big Lake National Wildlife Refuge is an 11,038 acre (45 km²) wildlife refuge located in Mississippi County, Arkansas managed by the United States Fish and Wildlife Service.

Big Lake National Wildlife Refuge was created in 1915 by President Woodrow Wilson after local residents became concerned that agricultural interests were destroying the natural environment of the area. It is situated 2 miles east of Manila, Arkansas. 5,000 acres (20 km²) of Big Lake is classified as a National Natural Landmark and 2,100 acres (8 km²) are classified as wilderness. The refuge consists of 5,250 acres (21 km²) of swampland, 2,600 acres (11 km²) of open water, 2,100 acres (8 km²) of bottomland hardwoods, 3300 acres (13 km²) of marsh, and 282 acres (1 km²) of other types.

The area that makes up the refuge was originally part of a free-flowing river system but the New Madrid Earthquakes of 1811 and 1812 changed the topography into the swampy wetlands seen today.

The refuge was once a portion of the Mississippi River but now the Little River flows through the refuge. A large network of man-made ditches in the Missouri bootheel region drain 2,000 miles (3,000 km) of farmland through the refuge. This non-natural drainage adversely affects the refuge itself.

Big Lake plays host to wintering and migrating ducks. The area is also the habitat for the bald eagle and osprey.