Recent advancements in cancer biology have revealed molecular changes associated with carcinogenesis and chemotherapeutic exposure. The available information is being gainfully utilized to develop therapies targeting specific molecules involved in cancer cell growth, survival, and chemoresistance. Targeted therapies have dramatically increased overall survival (OS) in many cancers. Therefore, developing such targeted therapies against oral squamous cell carcinoma (OSCC) is anticipated to have significant clinical implications. In the current work, we have identified drug-specific sensitivity-related prognostic biomarkers (BOP1, CCNA2, CKS2, PLAU, and SERPINE1) using gene expression, Cox proportional hazards regression, and machine learning in OSCC. Dysregulation of these markers is significantly associated with OS in many cancers. Their elevated expression is related to cellular proliferation and aggressive malignancy in various cancers. Mechanistically, inhibition of these biomarkers should significantly reduce cellular proliferation and metastasis in OSCC and should result in better OS. It is pertinent to note that no effective small-molecule candidate has been identified against these biomarkers to date. Therefore, a comprehensive in silico drug design strategy assimilating homology modeling, extensive molecular dynamics (MD) simulation, and ensemble molecular docking has been applied to identify potential compounds against identified targets, and potential molecules have been identified. We hope that this study will help in deciphering potential genes having roles in chemoresistance and a significant impact on OS. It will also result in the identification of new targeted therapeutics against OSCC.