Background and objective The appearance of highly effective and low toxic drugs enables an increasing number of advanced non-small cell lung cancer (NSCLC) patients to receive third-line therapy. No other standard choice for third-line therapy aside from erlotinib is possible. This study respectively explores the efficacy and safety of single chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), and doublet chemotherapy in advanced NSCLC third-line treatment. Methods This study included 115 NSCLC patients in the stage IIIb or IV who were retrospectively reviewed to investigate the differences of survival time between different treatments. Univariate and multivariate analyses were conducted based on the Kaplan-Meier method and Cox proportional-hazards model. Results The median progression free survival (PFS) values in the single agent, EGFR-TKIs and doublet groups were 2.30, 3.17 and 2.37 months, respectively (P=0.045). The median overall survival from the initiation of the third-line treatment were 8.00, 10.40 and 7.87 months in the three groups (P=0.110). The rates of stage III-IV toxicities were 33.3%, 18.2% and 68.8% (P<0.001), respectively. After the third-line treatment, the PFS was significantly increased in patients with a performance status (PS) of 0 to 1 (P<0.001), and the survival time was prolonged in patients who never smoke (P=0.011), have good PS (P<0.001), and have disease control after both first- and second-line treatments (P=0.044) using multivariate analysis. Conclusion Advanced NSCLC patients who never smoke, have good PS scores, and have good disease control from the first- and second-line therapies could benefit more in third-line treatment. EGFR-TKIs therapy showed increased PFS compared with single and doublet agents.