AIM: To investigate the application value of immunotherapy combined with anti-angiogenic drugs and chemotherapy in negative driver gene and advanced non-small cell lung cancer (NSCLC). METHODS: A total of 48 patients with advanced NSCLC and negative driver genes were included and randomly divided into two groups according to 1:1. The observation group received immunotherapy combined with anti-angiogenic drugs and chemotherapy. The control group received conventional standard chemotherapy. The differences between the two groups were analyzed in drug toxicity, side effects and survival status. RESULTS: Objective response rate (ORR) and disease control rate (DCR) were compared to evaluate the short-term efficacy. There was no statistical difference in ORR between the two groups. DCR in the observation group was higher than that in the control group, the difference was significant (P<0.05). The probability of hypertensive proteinuria and hand-foot syndrome in the observation group was significantly higher than that in the control group (P<0.05). Compared with the control group, the observation group could prolong the mPFS mOS of the patients (P<0.05). CONCLUSION: Immunotherapy combined with anti-angiogenic drugs and chemotherapy can improve the efficacy of negative driver gene and advanced NSCLC, which is tolerated by patients and worthy of clinical application.