Scabies is an invasive skin condition caused by Sarcoptes scabiei mites. The present study investigates the antiscabies potential of coconut seed extract (CSE) in rabbits. GC-MS analysis of the seed oil identified 17 known compounds, while CSE phytochemical investigation afforded 4 known ones. The topical application of seed extract improved all signs of infection, and the improvement started 3 days post application. However, in vitro application of the extract caused 99% mortality of mites 1 day post application. Histopathological examination revealed the absence of inflammatory infiltration and hyperkeratosis of the epidermis, compared with ivermectin-treated groups which revealed less improvement. The mRNA gene expression results revealed a suppression of IL-1β, IL-6, IL-10, MMP-9, VEGF, and MCP-1, and an upregulation of I-CAM-1, KGF as well as TIMP-1. The docking analysis emphasized a strong binding of gondoic acid with IL-1β, IL-6, and VEGF with high binding scores of −5.817, −5.291, and −8.362 kcal/mol, respectively, and a high binding affinity of 3″(1‴-O-β-D-glucopyranosyl)-sucrose with GST with −7.24 kcal/mol. Accordingly, and for the first time, our results highlighted the scabicidal potential of coconut seed extract, which opens the gate for an efficient, cost-effective as well as herbal-based alternative for the control of scabies in rabbits.