Ferrets (Mustela putorius furo) are becoming increasingly popular as pets and are kept in households with other pet animals such as dogs and cats, from which they may catch flea infestations with the predominant flea species Ctenocephalides felis. In this study, the efficacy of imidacloprid/moxidectin spot-on (Advocate®/Advantage Multi™) was investigated in the therapy and prevention of flea infestation in ferrets. Sixteen adult ferrets of varying weights and ages and of both sexes were included. Ferrets were infested with 50 fleas each on days −7, −1, 7, 14, 21, and 28. On study day −6, the animals were randomized into two groups based on body weight and flea count. Each ferret allocated to group 1 was treated with 0.4 ml of imidacloprid 10%/moxidectin 1% (Advocate®/Advantage Multi™). The ferrets in group 2 remained untreated. Flea counts were performed by combing 24 to 48 h after infestation. The primary efficacy criterion was the reduction in the number of fleas at each time point post treatment compared to the ferrets in the untreated control group. On day 1, the therapeutic efficacy was 100%. The preventative efficacy was 100% at 1 and 2 weeks post treatment, and it was >97% and >90% at 3 and 4 weeks post treatment. No local or systemic side effects were observed in any of the ferrets treated.