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Simple Summary: Despite major advances in treating non-small-cell lung cancer (NSCLC), the five-year survival rates for patients without specific genetic mutations remain low. This study aims to find better ways to treat these patients. We focused on a protein called Aurora kinase A (AURKA), which our prior study suggested may play a role in modulating resistance to the common cancer drug cisplatin. We looked at how AURKA affects the sensitivity of NSCLC cells to platinum-based chemotherapy and radiation. In lab tests, AURKA levels increased after cisplatin treatment. Blocking AURKA with a drug called alisertib or using a genetic method made cisplatin and radiation more effective, causing tumors to shrink in mouse models. The treated cancer cells showed more DNA damage and underwent cell death. Blocking AURKA also increased markers that help the immune system recognize cancer. Our study suggests that combining AURKA inhibitors with other treatments could improve outcomes for NSCLC patients. Despite major advances in non-small-cell lung cancer (NSCLC) treatment, the five-year survival rates for patients with non-oncogene-driven tumors remain low, necessitating combinatory approaches to improve outcomes. Our prior high-throughput RNAi screening identified Aurora kinase A (AURKA) as a potential key player in cisplatin resistance. In this study, we investigated AURKA's role in platinum and radiation sensitivity in multiple NSCLC cell lines and xenograft mouse models, as well as its effect on immune checkpoints, including PD-L1, B7x, B7-H3, and HHLA2. Of 94 NSCLC patient tumor specimens, 91.5% tested positive for AURKA expression, with 34% showing moderate-to-high levels. AURKA expression was upregulated following cisplatin treatment in NSCLC cell lines PC9 and A549. Both AURKA inhibition by alisertib and inducible AURKA knockdown potentiated the cytotoxic effects of cisplatin and radiation, leading to tumor regression in doxycycline-inducible xenograft mice. Co-treated cells exhibited increased DNA double-strand breaks, apoptosis, and senescence. Additionally, AURKA inhibition alone by alisertib increased PD-L1 and B7-H3 expression. In conclusion, our study demonstrates that AURKA inhibition enhances the efficacy of platinum-based chemotherapy in NSCLC cells and modulates the expression of multiple immune checkpoints. Therefore, combinatory regimens with AURKA inhibitors should be strategically designed and further studied within the evolving landscape of chemo-immunotherapy. [ABSTRACT FROM AUTHOR]