Abstract: Background and Objective: Inhibition of PD-1/PD-L1 with small molecules has shown promise as a potential therapy for certain cancers. This study aimed to synthesize and evaluate the antineoplastic activity of thirty biphenyl-1,2,3-triazole hybrid analogues. Materials and Methods: The effectiveness of inhibitors against PD-1/PD-L1 binding was evaluated using Homogeneous Time-Resolved Fluorescence (HTRF), the CCK-8 assay to assess the ability of the compounds to inhibit tumor cell proliferation and the wound-healing assay to study cell migration and cell-cell interaction. Results: Current findings indicated that compounds 6d, 6e and 6h exhibit strong anti-proliferative activity against A549, MDA-MB-231 and HCC827 cancer cells via the non-immune pathway. Specifically, they displayed potent inhibitory effects against A549 cells, with IC50 values of 0.315±0.13, 0.821±0.07 and 0.576±0.15 μM, respectively, suggesting that they have potential as anti-lung cancer drugs. Despite their potent anti-tumor activity, our compounds showed only weak inhibition of the PD-1/PD-L1 interaction, as evaluated by HTRF analysis. Conclusion: Results of the present study indicated that compounds 6d, 6e and 6h have anticancer efficacy through both immunological and non-immune mechanisms, specifically by inhibiting the PD-1/PD-L1 combination.