Background: Neoadjuvant immunochemotherapy has been proved effective in resectable NSCLC, while its role in unresectable stage IIIB NSCLC remains controversial. This study aims to demonstrate the efficacy and safety of neoadjuvant immunochemotherapy sequential surgical resection in initial unresectable stage IIIB NSCLC patients. Methods: This multicenter study retrospectively analyzed 59 patients with initial unresectable stage IIIB NSCLC who received induction pembrolizumab combined with chemotherapy between June 2019 and April 2022. The clinical characteristics, radiological and pathological response and survival outcomes were collected and evaluated. Results: A total of 59 initial unresectable stage IIIB NSCLC patients were identified and divided into the surgery group (n = 23) and non-surgery group (n = 36) with a median follow-up time of 15.0 months. The median PFS/DFS of surgery group was significantly longer than that of non-surgery group (not reached versus 15.5 months, p = 0.0031). The median OS was not reached in both groups, overall survival rate was 100% (23/23) in surgery group and 83.3% (30/36) in non-surgery group. Pathological analysis suggested that 13 of 23 patients (56.5%) achieved major pathological response (MPR) or pathological complete response (pCR), and more squamous cell carcinoma cases were observed in MPR group compared to non-MPR group (p = 0.034). Of 23 patients in surgery group, all patients had a R0 resection, no surgical-related mortality was recorded, only 3 patients (13.0%) experienced any postoperative complications. Conclusions: Surgical resection after neoadjuvant immunochemotherapy is beneficial in the survival outcome of initial unresectable stage IIIB NSCLC patients, with a high MPR rate and good surgical safety.