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In human history

Native Americans have long considered the muskrat to be an important animal. Some predict winter snowfall levels by observing the size and timing of muskrat lodge construction.

In several Native American creation myths, the muskrat dives to the bottom of the primordial sea to bring up the mud from which the earth is created after other animals have failed in the task.

Muskrats have sometimes been a food resource for North Americans. In the southeastern portion of Michigan, a longstanding dispensation allows Catholics to consume muskrat as their Friday penance, on Ash Wednesday, and on Lenten Fridays (when the eating of flesh, except for fish, is prohibited); this tradition dates back to at least the early 19th century. In 2019, it was reported that a series of muskrat dinners were held during Lent in the areas along the Detroit River, with up to 900 muskrats being consumed at a single dinner. The preparation involved the removal of the musk glands and the gutting and cleaning of the carcass before the meat was parboiled for four hours with onion and garlic and finally fried.

Muskrat fur is warm, becoming prime in northern North America at the beginning of December. In the early 20th century, the trapping of the animal for its fur became an important industry there. During that era, the fur was specially trimmed and dyed to be sold widely in the US as "Hudson seal" fur. Muskrats were introduced at that time to Europe as a fur resource and spread throughout northern Europe and Asia.

In some European countries, such as Belgium, France, and the Netherlands, the muskrat is considered an invasive pest, as its burrowing damages the dikes and levees on which these low-lying countries depend for protection from flooding. In those countries, it is trapped, poisoned, and hunted to attempt to keep the population down. Muskrats also eat corn and other farm and garden crops growing near water bodies.

Royal Canadian Mounted Police winter hats are made from muskrat fur.