Leishmaniasis, a neglected tropical disease caused by Leishmania parasites, remains a significant global health challenge, necessitating the discovery of novel therapeutic agents. In this study, six Waleed pyrimidine (WP) derivatives, WP-1 (2-methyl-4-phenylpyrimidine-5-carboxylic acid) and WP-4 (2,4-dimethylpyrimidine-5-carboxylic acid) among them, were evaluated for their antileishmanial activity through in vitro, in vivo, molecular docking, pharmacokinetic, and toxicological assessments. The compounds exhibited significant inhibitory effects on the Leishmania DHFR enzyme, with WP-1 and WP-4 demonstrating the highest binding affinities and potent antileishmanial activity. Both compounds were further analyzed for their pharmacokinetic properties, revealing favourable profiles such as high gastrointestinal absorption, the ability to cross the blood-brain barrier (BBB), and optimal log P values. Toxicological evaluations using advanced in silico platforms indicated no significant safety concerns, making WP-1 and WP-4 viable candidates for therapeutic development. Furthermore, in vivo studies in murine models confirmed their effectiveness, with WP-4 emerging as the most promising compound based on lower IC50 values and improved survival rates.