Primary predators of porcupines include coyotes and bobcats who like their large body size and ample supply of meat. Some wolves and owls also hunt porcupines. Relative to other rodents, porcupines have a small number of enemies because other animals don't like to deal with their sharp quills.

Humans pose one of the biggest threats to porcupines. Many porcupines are killed on the roads when they are hit by motor vehicles. Some people hunt porcupines for food. Because porcupines cause damage to trees, seedlings, crops, tires and powerlines due to their chewing activity, people regard them as pests and use trapping or poisoning to eliminate them.