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Dengue disease is a mosquito vector borne viral disease which is transmitted mostly by the Aedes aegypti mosquito vector species. Other viral diseases such as chikungunya, yellow fever and zika are also caused by this vector. After feeding on a DENV-infected person, the virus replicates in the mosquito midgut then it distributes to other tissues. Medicinal plant species contains wide series of phytochemicals such as primary and secondary metabolites that produce biological activities and defenses against mosquitoes. In the current study, a methanol leaf extract of Aegle marmelos was assessed for larvicidal efficacy and midgut alteration of third instar Ae. aegypti larvae. After the larvicidal bioassay, the probit analysis identified Lc50 in this extract that killed the larvae at the concentration of 49 ppm. Proteomic analysis and in-silico studies revealed that the predicted protein could disrupt the larvae midgut because of the Aegle marmelos natural bioactive compounds and secondary metabolites. Our approach is to identify the inhibitor proteins that bound to midgut of Ae. aegypti larvae after treatment with the Aegle marmelos bioactive compounds by using computational proteomic analysis.