Ectoparasites poses potential hazards and are a constant challenge for veterinarians and pet owners worldwide. This clinical field study was conducted to assess the efficacy of different topical spoton formulations against ticks and fleas in naturally infected dogs admitted for clinical examination at the Veterinary Hospital, Faculty of Veterinary Medicine, Sharkia Governorate, Egypt. Forty dogs showed ectoparasites infestation were enrolled. These dogs were divided into four groups (ten each). Group1 (G1) considered as untreated control. The other three groups (G2, G3, and G4) were treated with fipronil 9.8% (Fipron spot-on solution), a combination of 9.8% fipronil/(S)-9.8% methoprene (Frontline Plus®), and imidacloprid/permethrin (K9-Advantix®), respectively. Clinical (all the dogs were clinically monitored throughout the experiment), parasitological (ticks and fleas (adult and eggs) were counted and identified on days 0, 1, 2, 7, 15, 21, 30, and 45 after treatment, and zootechnical (live-weight gain) analyses were conducted. Throughout the experiment, no adverse symptoms were observed in any of the treated animals. The synergistic effect of each topical spot-on was compared for eliminating ticks and fleas, aiming to obtain the ideal treatment model. Our results suggest that fipronil/(S)-methoprene outperformed fipronil alone in controlling ticks and fleas in naturally infested dogs. Also, it may be productive in the struggle against different tick and flea species infesting dogs as it gives protection for at least four weeks. In comparison to the other two topical spot-on formulations used in this study, imidacloprid/permethrin was the least effective, particularly against fleas. Overall, because these ectoparasites concern animal welfare and human health, this study underlines the importance of continued ectoparasites monitoring and educating pet owners about the impacts of flea and tick infestations as well as pathogenic hazards.