Advanced non-small cell lung cancer (NSCLC) represents a significant challenge in oncology, particularly when accompanied by distant metastases or when surgical resection is not feasible. These conditions are typically associated with poor prognosis and variable responses to treatment. Traditional chemotherapy, while commonly used, has limited efficacy and is often associated with substantial adverse effects, which can compromise survival outcomes. In recent years, targeted therapy and immunotherapy have emerged as promising alternatives for the treatment of advanced NSCLC. This retrospective cohort study aimed to evaluate the efficacy and safety of a combination regimen consisting of carboplatin, paclitaxel, bevacizumab, or gefitinib in patients with advanced NSCLC. A total of 312 patients, diagnosed and treated between January 2019 and December 2023, were included in the analysis. Patients were categorized into non-epidermal growth factor receptor gene mutation group (Group A + Group B) and epidermal growth factor receptor gene mutation group (Group C + Group D) according to gene mutation. The treatment regimens were divided into 4 groups: Group A (carboplatin + paclitaxel combined with bevacizumab treatment), Group B (carboplatin + paclitaxel treatment), Group C (carboplatin + paclitaxel combined with gefitinib treatment), and Group D (carboplatin + paclitaxel treatment). The results demonstrated that the experimental groups (A and C) exhibited significantly superior short-term efficacy compared to the control groups (B and D), with notable improvements in both the objective response rate and disease control rate (P < .05). Survival analysis further revealed that the median progression-free survival and overall survival were significantly longer in Groups A and C than in Groups B and D (P < .001). While the experimental groups experienced a higher incidence of adverse events, particularly hypertension, diarrhea, constipation, and rash, most of these were manageable. In conclusion, the combination of carboplatin, paclitaxel, bevacizumab, or gefitinib significantly improved progression-free survival and overall survival in patients with advanced NSCLC, offering superior efficacy over conventional regimens, with manageable side effects. These findings warrant further investigation to confirm the long-term benefits and optimize treatment strategies for advanced NSCLC.