Non-small cell lung cancer (NSCLC) patients with pleural dissemination are generally contraindicated for surgery. This study aimed to investigate the survival benefits of primary tumor resection for NSCLC patients with unexpectedly detected pleural disseminated nodules during thoracotomy in the era of targeted therapy. Of the 4984 patients with NSCLC who underwent surgery without induction therapy between 2000 and 2021, we retrospectively evaluated 90 (1.8%) patients with unexpectedly detected pleural disseminated nodule. Survival analyses were performed with Kaplan-Meier methods and Cox proportional hazards regression. Among the evaluated patients, 58 were male, the median age was 67, and 77 (86%) were diagnosed with adenocarcinoma. Exploratory thoracotomy was performed in 21 (23%), and primary tumor resection was performed in 69 (77%) patients, including pneumonectomy in four, lobectomy in 39, and sublobar resection in 26. Epidermal growth factor receptor gene mutation and anaplastic lymphoma kinase rearrangement were detected in 33 (37%) and 4 (4%) cases, respectively. Among them, 31 patients received targeted therapy. The overall survival (OS) was not significantly different between patients with primary tumor resection and exploratory thoracotomy (5-year OS rate: 30.2% vs. 27.8%, p = 0.81). Multivariable analysis revealed that sex (p = 0.02) and targeted therapy (p < 0.01) were independent prognostic factors for OS. Survival outcomes in patients who received targeted therapy were significantly better regardless of primary tumor resection. Primary tumor resection might not affect the survival in NSCLC patients with unexpectedly detected pleural disseminated nodules in the era of targeted therapy.