In recent decades, the majority of human plague cases (caused by Yersinia pestis) have been reported from Africa. In an effort to reduce the risk of the disease in this area, we evaluated the efficacy of a host-targeted rodent bait containing the insecticide imidacloprid for controlling fleas on house-dwelling commensal rodents in a plague-endemic region of northwestern Uganda. Results demonstrated that the use of a palatable, rodent-targeted, wax-based bait cube was effective at reducing the prevalence of fleas on commensal rodents and flea burdens on these animals at day 7 postbait exposure, but lacked significant residual activity, allowing flea populations to rebound in the absence of additional bait applications. Our results indicate the use of a palatable host-targeted bait block containing imidacloprid was an effective technique for quickly reducing flea numbers on rodents in northwest Uganda and, thus, could be useful for lowering the potential risk of human flea bite exposures during plague outbreaks if applied continuously during the period of risk.