Objective To explore the efficacy of different second-line treatment strategies in the real world after progression of first-line immunotherapy and its combination therapies in patients with driver gene-negative advanced non-small cell lung cancer （NSCLC）. Methods A retrospective analysis was conducted on the clinical data of 93 driver gene-negative advanced NSCLC patients who received first-line immunotherapy and its combination therapies from January 1，2018 to December 31，2023 at the First Affiliated Hospital of Xinxiang Medical University and Xinxiang Central Hospital. Patients were categorized into immune checkpoint inhibitors （ICIs）-resistant （n=43） and ICIs-responsive （n=50） groups according to whether progression free survival （PFS） exceeded 6 months after first-line treatment. Patients were categorized into ICIs-treated （n=55） and non-ICIs-treated （n=38），anti-angiogenic-treated （n=51） and non-anti-angiogenic-treated （n=42） groups according to the different second-line treatment strategies after progression of first-line immunotherapy and its combination therapies. The median PFS2 （mPFS2） and median overall survival （mOS）2 after second-line treatment of each group were compared. The Kaplan-Meier method was used for survival analysis. Results The mPFS2 and mOS2 of 93 advanced NSCLC patients who progressed after first-line ICIs treatment were 4.9 months （95%CI： 4.1-5.7 months） and 14.7 months （95%CI： 11.2-18.2 months）. The mPFS2 of patients in the first-line ICIs-responsive and ICIs-resistant groups were 6.0 and 3.8 months，respectively，with no statistically significant difference （χ2=2.00，P=0.157），and the mOS2 were 25.3 and 11.3 months，respectively，with a statistically significant difference （χ2=12.13，P<0.001）. The mPFS2 of patients in the second-line ICIs-treated group and the non-ICIs-treated group were 5.2 and 4.6 months，respectively，with no statistically significant difference （χ2=0.16，P=0.687）. The mOS2 were 15.1 and 12.7 months，respectively，with no statistically significant difference （χ2=0.01，P=0.930）. The mPFS2 of patients in the second-line anti-angiogenic-treated and non-anti-angiogenic-treated groups were 4.5 and 6.0 months，respectively，with no statistically significant difference （χ2=0.41，P=0.525），the mOS2 were 14.7 and 16.8 months，respectively，with no statistically significant difference （χ2=0.01，P=0.943）. Conclusions After progression of first-line ICIs therapy in patients with driver gene-negative advanced NSCLC，first-line ICIs-responsive patients have significantly longer OS after second-line treatment compared with ICIs-resistant patients. The efficacy of second-line therapy in patients after progression of first-line ICIs therapy does not show significant differences due to the type of treatment strategies.