Background: Dogs’ health and welfare enhancement can be achieved using some prophylactics and immunization go with strict hygienic and optimum biosecurity measures. Aim: Exploration of the insecticidal action of Phoxim® for combating Rhipicephalus sanguineus infestation in dogs and its prophylactic influences on the blood indices, biochemistry, antioxidant enzymes, and cortisol hormone in healthy and infested dogs. Methods: Twenty German Shepherd male dogs at one year old and 44.0 kg were divided randomly into four groups of five dogs in four separate Kennels with optimum biosecurity measures. The 1st group (G1) was artificially infested with R. sanguineus and treated with Phoxim®, the 2nd (G2) was non-infested and treated with Phoxim®, the 3rd (G3) was infested with R. sanguineus and not treated (positive control), and the 4th (G4) was accounted as negative control (non-infested and non-treated). A total of 160 (80 whole blood and 80 sera) samples were collected. Results: Parasitological examination revealed prominent characteristic features of R. sanguineus such as a distinct anal groove, the basis capitulum is hexagonal and lateral, the palpi are short, the second segment of the palpi as long as wide and not produced laterally, and the spiracular plate is comma-shaped and consists of stigma, peritreme, and tail. The results conveyed highly significant (p < 0.01) enhancement in erythrocytes, leukocytes, hematohiston, hematocrit, hemoglobin centering, granulocytes, alanine aminotransferase, random blood sugars, triglycerides, and total cholesterol, and highly significant (p < 0.01) declines of all measured antioxidant enzymes in treated non-infested dogs. Conclusion: Phoxim® proved efficient insecticidal activity with optimum safety and can be brought into play in the prophylactic biosecurity measures installed to eradicate external parasitism in dogs.