Cotton rats (Sigmodon hispidus) are widely used as animal models for infectious disease and immunological research. They emulate many aspects of human disease pathogenesis, and the introduction of cotton rat-specific immunological reagents, cell lines and sequencing of relevant genes have all helped to increase the popularity of this disease model. However, the use of cotton rats is problematic owing to their propensity for aggressive responses when handled, which can lead to escape, increased stress to the animals, and bites to staff. When cotton rats are co-housed, which is recommended under current social housing guidelines, these risks are increased. Here, we describe a method of isoflurane anesthesia induction in the home cage that reduces the risk of animal escape, minimizes stress during induction, and provides additional safety for staff. The method uses inexpensive materials that are widely available and can be easily disinfected. Our method also eliminates the need for expensive and cumbersome machines traditionally used with anesthetic chambers, and uses a minimal amount of inhalant anesthetic, saving resources and protecting staff from inhalation of leaked gas.