Colorectal cancer (CRC) is the second deadliest diseases next to lung cancer. Cisplatin is the first generation platinum based alkylating agent using for treatment of advance CRC patients. Continuous usages of cisplatin lead to resistance which limits its therapeutic efficacy. Recent research is focused on studying the chemotherapeutic efficacy of the phytochemicals as they are less toxic compared to the conventional chemotherapeutic drugs. Neferine is a bisbenzylisoquinoline alkaloid extracted from the embryo of Nelumbo nucifera. The anticancer and chemosensitizing effect of neferine has been well reported in several cancer cells. However, there are no reports on the chemosensitizing effect of neferine on cisplatin-resistant colorectal cancer cells (CRCs). Hence, the present study aims at identification of target proteins responsible for cisplatin-resistance in colorectal cancer cells. The present investigation elucidates the specific interaction of neferine with various cell surface receptor proteins related to cisplatin-resistance, multi-drug resistance (MDR) proteins, signal transduction protein and transcription factors via molecular docking approach. The interaction between neferine and the target proteins of cisplatin-resistant colorectal cancer was analyzed through Schrodinger Maestro 11.9 module. From our docking studies we could suggest that neferine is most active for insulin-like growth factor-1 receptor (IGF1R), fibroblast growth factor receptor-2 (FGFR2), zinc finger protein SNAI1 (SNAIL1), signal transducer and activator of transcription-3 (STAT3) and transforming growth factor beta receptor-1 (TGFβR1) when sorted according to their docking score.