Human scabies, a highly contagious parasitic skin infestation caused by Sarcoptes scabiei var. hominis mites, spreads rapidly through interpersonal contact. This study employed an integrated network pharmacology and molecular docking approach to identify shared therapeutic targets of seven structurally diverse Amaryllidaceae alkaloids (1–7) and evaluate their anti-scabies potential. A scabies-associated protein network was constructed, revealing interleukin-6 as the highest-degree node and a pivotal therapeutic target, alongside caspase-3. Sub sequent molecular docking analyses assessed the binding affinities and interaction stability of two promising alkaloids, narcissidine methyl ether (2) and crinine (3), with IL-6 and glutathione S-transferase (GST). Narcis sidine methyl ether demonstrated the strongest binding affinity to IL-6 (ΔG =–4.618 kcal/mol), while both compounds exhibited notable interactions with GST (ΔG =–5.917 and 4.885 kcal/mol, respectively). Computational screening confirmed their adherence to Lipinski’s and Veber’s rules, indicating favorable drug likeness properties. In vitro and in vivo experiments revealed significant acaricidal activity, with narcissidine methyl ether showing potent scabicidal effects. Histopathological evaluation of treated rabbit models demon strated marked improvement in ear auricle skin architecture three weeks post-treatment, supporting the thera peutic efficacy of both compounds. These findings highlight narcissidine methyl ether and crinine as promising anti-scabietic drugs, offering a foundation for future preclinical studies.