Background: Previously, the clinical value of seven autoantibodies (p53, PGP9.5, SOX2, GAGE7, GBU45, MAGEA1, and CAGE) has been surveyed in our pilot observation and other published studies. Herein, we aimed to further investigate the role of these autoantibodies in the diagnosis and staging of LC. Methods: We included a total of 135 individuals, who were divided into a LC group and a control group according to the final diagnosis. Seven autoantibody detection kits were used (ELISA method) for the expression measurement. The patients' demographics information (e.g., age, gender, and smoking history) were also documented. Results: Among the seven types of autoantibodies, only P53 and GBU4-5 were significantly increased in the LC group compared to the controls. Also, the P53 autoantibody was markedly different among the various subtype groups. Meanwhile, the GBU4-5 level was significantly higher in the small cell lung cancer (SCLC) patients compared to patients with adenocarcinoma (ADC). Autoantibodies against PGP9.5, SOX2, GBU4-5, and CAGE were found to be associated with stages. Their expressions were notably higher in the advanced stage (IV) versus early stages (I-II). Using logistic regression, the outcomes of LC prediction and stage prediction showed that the area under curve (AUCs) of the receiver operating characteristic (ROC) curves were 743 and 0.798, respectively. Conclusions: In summary, our study confirmed the diagnostic value of tumor-associated autoantibodies, which may be useful as latent tumor markers to facilitate the detection of early LC. Single autoantibody testing is not yet sufficient in LC cancer screening, and the combined detection of autoantibodies can improve the sensitivity of detection compared with single antibody detection, especially for P53, PGP9.5, SOX2, GBU4-5, and CAGE autoantibodies.