Sylvatic plague, a primarily flea-borne zoonosis, is a significant threat to prairie dogs (Cynomys spp., PDs) and their specialized predators, endangered black-footed ferrets (Mustela nigripes, BFFs). Host-fed fipronil baits have proven effective in controlling fleas on PDs for the purposes of plague mitigation and BFF conservation. Currently, annual treatments are the norm. We tested the long-term efficacy of fipronil bait treatments with black-tailed PDs (C. ludovicianus, BTPDs) and BFFs in South Dakota, USA. During 2018–2020, we provided BTPDs on 21 sites with grain bait formula, laced with 0.005% fipronil (50 ​mg/kg); 18 non-treated sites functioned as baselines. In 2020–2022, we live-trapped, anesthetized, and combed BTPDs for fleas. Flea control was significant for at least 639–885 days. Flea abundance on the treated sites was < 0.5 fleas/BTPD for ∼750 days. During 2020–2022, we sampled BFFs for fleas on 4 BTPD colonies treated with fipronil grain bait and 8 non-treated colonies. Flea control was significant with BFFs, but flea abundance began to rebound within ∼240 days post-treatment. When feasible, the combination of insecticide treatments, such as fipronil baits, and BFF vaccination against plague provide a “two-pronged” protection approach for these endangered carnivores. If fipronil bait treatments are less effective with predatory BFFs than PDs, as found herein, the “two-pronged” approach might be used to protect BFFs and biennial fipronil bait treatments might be used to protect PDs. If BFF vaccination is not possible, or few BFFs can be vaccinated, annual fipronil bait treatments might be used as a precaution to protect BFFs. Flea densities might be surveyed to determine when/where more frequent treatments seem useful.