Purpose <p>Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating adverse effect associated with the administration of various neurotoxic chemotherapeutic agents. The pathogenesis of CIPN is multifactorial, involving mitochondrial dysfunction, oxidative stress, microtubule disruption, ion channel alterations, etc. Notably, in ion channel alterations, the overexpression of the transient receptor potential vanilloid 1 (TRPV1) receptor has been implicated as a critical contributor to CIPN pathophysiology. Currently, there is no drug approved by the US FDA specifically for CIPN. The American Society of Clinical Oncology (ASCO) recommends duloxetine as a management option for CIPN.</p> Methods and Results <p>In the present study, extensive in silico investigations were conducted to identify potential drug candidates for CIPN management by exploring the PubChem database for compounds similar to duloxetine, as well as Ca²⁺ ion channel inhibitors from the Enamine database. Protein with PDB ID 8GFA, possessing a unique inhibitor of hTRPV1, was chosen for study. A duloxetine-based pharmacophore model was generated and used to screen compound libraries. The screened compounds further underwent a virtual screening workflow (VSW), and the top eight compounds were then assessed for parameters such as MM-GBSA and ADMET. To further validate the interactions of the top three compounds, a molecular dynamics (MD) simulation was performed over 100 ns. Density functional theory (DFT) calculations of the top three compounds and duloxetine were performed, and the HOMO, LUMO, energy gap, and electrostatic potential (ESP) were calculated. Enamine Calcium 8966 excelled in docking, MM-GBSA, ADME analysis, MD simulations, and MM-PBSA.</p> Conclusion <p>These findings support Enamine Calcium 8966 as a potential hTRPV1-targeted therapeutic for CIPN, meriting further experimental evaluation.</p>