The available anthelmintic medications are ineffective against many helminths of veterinary importance and controlling such resistant parasites is challenging. In this study, we focused Ancylostoma caninum’s anthelmintic resistance and targeted its metalloprotease-2 (Ac-MTP-2). A. caninum is a canine hookworm that infects dogs, cats, and also humans. The phytochemicals of common plants, Catharanthus roseus (Periwinkle) and Vernonia amygdalina (Bitter leaf) were evaluated for their anthelmintic potential against Ac-MTP-2. The application of Computer-aided drug discovery fastens the traditional drug discovery process and facilitates the prompt finding of newer lead molecules. The docking study performed showed that ajmalicine (-9.4 kcal/mol), serpentine (-9.2 kcal/mol), raubasin (-9.12 kcal/mol), vernolide (-8.09 kcal/mol), and hydroxyvernolide (-8.04 kcal/mol) had the lowest binding of all the molecules. The present study suggests a few promising in silico anthelmintic actions of a few phytochemicals. The ability of these compounds to act as an anthelmintic drug is to be evaluated further by in vitro and in vivo studies.