Demodicosis is common in dogs and is caused by proliferation of commensal Demodex canis mites. To evaluate the efficacy of sarolaner in combination with moxidectin and pyrantel (SMP) for the treatment of generalised demodicosis in dogs. One hundred and thirty dogs with generalised demodicosis. In two separate randomised masked studies (laboratory and field studies), dogs received monthly oral SMP or afoxolaner + milbemycin oxime (AM). In the laboratory study, dogs received three monthly treatments with biweekly mite counts and clinical evaluations. In the field study, mite counts and clinical evaluations were performed monthly and treatments were administered until two consecutive skin scrapings were negative. Both products were tolerated well. In the laboratory study, mite counts for SMP were significantly (p < 0.001) reduced by 88.8% on Day (D)14, by 99.2% on D29, and no live mites were detected thereafter with no statistically significant difference (p = 0.96) between the two treatment groups. In the field study, SMP provided 92.4%, 98.1%, 100% and 100% reduction in arithmetic mean live mite counts on D30, D60, D90 and D120, and was non-inferior to the control product on D30 and D60. Clinical signs of demodicosis improved in all dogs. Monthly administration of SMP was effective for the treatment of generalised demodicosis in dogs as it eliminated Demodex mites after two monthly treatments in the laboratory study, and at most after three monthly treatments in the field study.