〔Abstract〕 Objective To study the efficacy of pemetrexed in patients with advanced non-small cell lung cancer who failed chemotherapy and targeted therapy. Methods 50 patients with advanced non-small cell lung cancer who failed chemotherapy and targeted therapy in Cenxi people's Hospital from February 2019 to February 2020 were selected as the research object. They were randomly divided into observation group and control group, with 25 cases in each group. The control group was treated with conventional drugs (docetaxel) and the observation group was treated with pemetrexed. The clinical therapeutic effects and adverse reactions (hair loss, anemia, nausea, vomiting and diarrhea) were compared between the two groups. Results The total effective rate was 92% in the observation group and 68% in the control group (P < 0.05); The incidence of adverse reactions in the observation group was significantly lower than that in the control group (P < 0.05). Conclusion Pemetrexed should be selected in the treatment of advanced non-small cell lung cancer patients who failed chemotherapy and targeted therapy, so as to improve the treatment efficiency and reduce the occurrence of adverse reactions.