Background and objectives <p>Osteosarcoma (OS) is a malignant bone tumor originating directly from bone tissue, predominantly affecting adolescents. Cisplatin (DDP)-based chemotherapy is commonly used in the treatment of OS, but the emergence of DDP resistance poses a significant challenge to effective management. The study aimed to investigate the role of circRNA VANGL1 (circVANGL1) in mediating DDP resistance in OS <i>in vitro.</i></p> Materials and methods <p>The OS cell lines U2OS and MG-63 were used, and DDP-resistant cell models (U2OS-DR and MG-63-DR) were established. Transfection with circVANGL1 siRNA was performed to silence circVANGL1 expression, and its impact on cell proliferation, apoptosis, DDP resistance, and miR-145-5p level was studied. Fluorescence in situ hybridization was employed to localize circVANGL1. TargetScan prediction was utilized to identify the interaction between circVANGL1 and miR-145-5p. Co-transfection experiments of si-circVANGL1 with anti-miR-145-5p or E2F3 overexpression vector (E2F3-oe) were conducted to assess their effects on DDP-resistant cells.</p> Results <p>Compared to the parental cells, the expression of circVANGL1 was increased by approximately 2.2-fold and 2.5-fold in U2OS-DR and MG-63-DR cells, respectively (<i>P</i> &lt; 0.01). Transfection with si-circVANGL1 effectively suppressed cell proliferation and DDP resistance while promoting apoptosis in DDP-resistant cells. circVANGL1 is transferred via exosomes and primarily localized in the cytoplasm of U2OS and MG-63 cells. TargetScan prediction indicated a target relationship between circVANGL1 and miR-145-5p. Co-transfection of si-circVANGL1 with anti-miR-145-5p or E2F3-oe counteracted the changes in proliferation and apoptosis observed with si-circVANGL1 transfection alone in DDP-resistant cells.</p> Conclusion <p>In vitro findings preliminarily suggest that exosomal circVANGL1 may promote DDP resistance in OS cells by regulating the miR-145-5p/E2F3 axis.</p>