Objective <p>The objective of this study is to evaluate the anticancer activity of lenvatinib and zinc oxide nanoparticles (ZnO-NPs) separately and in combination and whether ZnO-NPs can reduce resistance to lenvatinib treatment.</p> Methods <p>TEM, SEM, Zeta, DLS, UV, FTIR, and XRD performed to characterize ZnO-NPs. Fifty mature female Swiss albino mice bearing solid Ehrlich carcinoma (SEC) were randomly divided into five equal groups: Negative control, SEC, Lenvatinib, ZnO-NPs, and Lenvatinib + ZnO-NPs. All treatments were administered for 4 weeks.</p> Results <p>A decrease in tumor volume (458.6 mm³<b>)</b> and an increase in tumor growth inhibition (67.6%) were observed in the combination groups. In the combination group, there was a decrease in serum ALT and AST levels. Besides, there was a significant increase in reactive oxygen species (ROS), malondialdehyde (MDA) and tumor necrosis factor-alpha (TNF-α) accompanied by depletion in superoxide dismutase (SOD) and catalase, in tumor tissues. Notably, the anti-apoptotic marker Bcl-2 significantly decreased, while caspase-3 and caspase-9 levels in blood samples and caspase-3 expression in tumor tissues increased significantly. Cell cycle research revealed a G2/M phase arrest in tumor samples. Additionally, Cyclin D1 expression (0.63) was significantly reduced by western blotting, and immunohistochemical staining showed lower Ki-67 levels (46.6%). Elevation of apoptosis and necrosis was confirmed by histopathological analysis of tumor sections. Also, histopathological examination of major organs (liver, kidney, heart, and spleen) showed no discernible damage.</p> Conclusion <p>According to these results, zinc oxide nanoparticles may increase lenvatinib's anticancer effectiveness by promoting apoptosis and inhibiting proliferation. Future clinical research may employ the combination because it seems to be both safe and effective.</p>