Objective <p>Non-small cell lung cancer (NSCLC) represents over 80% of lung cancer cases. Neoadjuvant therapy (NAT) improves overall survival (OS) of NSCLC patients. We explored clinicopathological significance of pre- and post-NAT CD47 and PD-L1 (SP142) changes [ΔCD47, ΔPD-L1 (SP142)] in stage IIIA-N2 NSCLC patients.</p> Methods <p>Totally 137 stage IIIA-N2 NSCLC patients underwent post-NAT surgery were selected, with tissues and clinical data collected. CD47 and PD-L1 (SP142) were determined by RT-qPCR and immunohistochemistry, with their relationships with chemotherapy efficacy and the tumor regression grade (TRG) score analyzed. The predictive value of CD47 and PD-L1 (SP142) for poor prognosis and their effects on OS and progression-free survival (PFS), and independent risk factors (IRFs) for poor 5-year prognosis were analyzed by receiver operating characteristic, Kaplan–Meier curves, and COX univariate/multivariate regression models.</p> Results <p>Post-NAT CD47 and PD-L1 (SP142) were reduced in stage IIIA-N2 NSCLC patients. Higher ΔCD47 and ΔPD-L1 correlated with worse chemotherapy efficacy. Post-NAT ΔCD47 and ΔPD-L1 (SP142) were reduced in patients with major pathological response. ΔCD47 and ΔPD-L1 positively correlated with TRG scores. Elevated ΔCD47, ΔPD-L1 (SP142) were IRFs for poor prognosis in NSCLC patients. The area under the curve of ΔCD47, ΔPD-L1 (SP142) and their combination for predicting NSCLC poor prognosis were separately 0.801, 0.797 and 0.891. Elevated ΔCD47 and ΔPD-L1 (SP142) shortened OS, PFS, and increased mortality risk in patients.</p> Conclusions <p>Post-NAT CD47 and PD-L1 (SP142) levels were reduced in IIIA-N2 NSCLC patients. ΔCD47 and ΔPD-L1 (SP142) levels linked to clinicopathological characteristics and predicted prognosis.</p> Graphical Abstract <p></p>