Sarcoptes scabiei var. cuniculi is one of the most important veterinary ectoparasites in rabbits and results in considerable loss of weight, productivity, and wool quality. The acaricidal activity of aqueous leaf extract of neem (CAN) and ivermectin (IVR) were evaluated in vitro and in vivo against S. scabiei var. cuniculi. Rabbits were classified into four groups (ten rabbits each). The first group (group 1) was designated as the negative control group. Each rabbit of the other groups was experimentally infested with 50 mites. One month post-infestation, the second group (group 2) was not treated and taken into account as the positive control group. The third group (group 3) was subcutaneously injected with 1 % IVR (200 μg/kg body weight, three times within a week interval). The fourth group (group 4) was treated topically with CAN (25 %) every 3 days for three consecutive weeks. Index scoring of lesions was described weekly. The number of live mites (larvae, nymphs, and adults) on each rabbit was counted on the 14th, 28th, and 42th day post-treatment (PT). Blood samples were taken 28 and 42 days PT for estimation of some chemical parameters. The body weight and cumulative body weight gain were recoded 14, 28, and 42 days PT. CAN (40 %) was highly efficacious against larvae of S. scabiei var. cuniculi as 100 % mortality was reached 24 h PT. On the other hand, all treated mites with CAN (20 %) and IVR died 48 h PT. The lethal values of CAN (LC50, LC90, LC95, and LC99) were 7.496, 14.67, 17.75, and 25.37 %, respectively, 48 h PT. Lesion scoring in groups 3 and 4 were significantly decreased (P ≤ 0.05), reaching 0.20 and 0.40, respectively, when compared with that of group 2 (4.00), 42 days PT. Twenty-eight days PT, the reduction percentages of mites infesting rabbits were 93.38 and 93.09 % for IVR and CAN, respectively. However, complete mite reduction was reached 42 days PT. Rabbits treated with CAN did not show signs of restlessness or irritation, respiratory signs, or inflammation on the eye and/or skin at the time of application or afterwards. Regarding biochemical analysis, the levels of aspartate aminotransferase, alanine aminotransferase, creatinine, and total cholesterol in rabbits treated with CAN were decreased significantly (P ≤ 0.05) than those of rabbits of the positive control group and those treated with IVR. On the other hand, the levels of total protein, albumin, and globulin of rabbits in group 4 were significantly (P ≤ 0.05) increased when compared with the corresponding values of groups 2 and 3. The body weight and cumulative body weight gain of rabbits treated with CAN were significantly increased (P ≤ 0.05) when compared with such values of groups 2 and 3, 28 and 42 days PT. The present data indicated that CAN had in vitro and in vivo acaricidal efficiency similar to that of IVR and improved the performance of rabbits without inducing adverse effects on treated rabbits; consequently, CAN could be suitable as a promising alternative acaricide for veterinary use.