Introduction: Dengue is hyperendemic in tropical and subtropical regions of the globe, particularly in urban and semi-urban areas. The dengue virus (DENV) NS2B/NS3 protease is considered an important protein which is responsible in viral maturation of DENV. So far, there are no specific medications for treatment of dengue. Therefore, research regarding dengue treatment is needed and one of potential targets is NS2B/NS3 protease. Potential inhibitors of NS2B/NS3 protease can be explored by using empirical data of medicinal plant. The data shows that Carica papaya, native plant in tropical area at Central America and South of Mexico, is often cultivated and used for medical purposes such as dengue. Objective: Therefore, the aim of this study was to explore and determine potential compounds in Carica papaya leaf as DENV NS2B/NS3 protease inhibitor based on in silico study. Methodology: Initial study was conducted by literature study to collect a list of compounds in C. papaya leaf. The 3D structure of 31 compounds was modeled with Avogadro 1.2.0 software and the geometrical optimization was done in ORCA 4.2.1 software. Then, the affinity towards DENV NS2B/NS3 protease was determined by molecular docking simulation using AutoDock 4.2 and MGLTools 1.5.7 software. Besides the affinity towards protease, the ADMET prediction was also conducted for the potential compounds to be developed as an oral drug. ADME prediction was conducted by SwissADME, while the toxicity prediction was conducted using VEGA 1.2.3 software. Results and Discussion: The docking simulation results showed that all compounds have affinity towards NS2B/NS3 protease by giving negative value of binding free energy. However, only 15 compounds fulfill the Lipinski’s Rule of Five. Further investigation regarding detail interaction and ADMET prediction was conducted by exploring the 7 best compounds which are dicoumarol, luteolin, apigenin, quercetin, coumaroylquinic acid, kaempferol, and caffeic acid. Conclusion: Based on affinity towards NS2B/NS3 protease and ADMET prediction, the best two compounds that are potential as candidates for oral anti-dengue drug are apigenin, kaempferol. These two compounds have similar conformation with native ligand of NS2B/NS3 protease and bind to a key residue of the NS2B/NS3 protease. These compounds were also chosen based on Lipinski’s Rule of Five that are related to the bioavailability as an oral drug and relatively low toxicity.