Introduction: Cancers of unknown primary (CUPs) present a diagnostic challenge as their origin is unidentified at diagnosis. Massive pleural effusion (MPE), indicative of lung metastasis in CUP, categorizes the condition into an unfavorable subset with a poor prognosis. Patients in this subset may exhibit a lower response to specific therapies. Case Presentation: A 62-year-old woman presented with cough, severe dyspnea, and MPE in the left lung. Thoracocentesis was performed, extracting 1,200 mL of hemorrhagic fluid, followed by the placement of an indwelling pleural catheter. The cytological examination of the pleural effusion indicated an adenocarcinoma, with immunohistochemistry revealing positive CK7 and negative CK20, Napsin A, and TTF-1. Additionally, elevated levels of Ca-125 (1,605 U/mL) and Ca 15-3 (242 U/mL) raised suspicion of gynecological malignancy. Thorax and abdominal CT scans, breast and thyroid ultrasounds showed no signs of malignancy, leading to the diagnosis of CUP. The patient’s performance status according to the Eastern Cooperative Oncology Group (ECOG) score was 4. Initial carboplatin 5 AUC and paclitaxel 175 mg/m2 administration resulted in improvement in performance status with ECOG score of 1, alleviation of dyspnea, reduction in pleural effusion 1 week after chemotherapy, with minimal effusion observed at 3 weeks, and Ca-125 levels decreased to 33.6 U/mL thereafter. Discussion: Empiric chemotherapy using carboplatin and paclitaxel is a feasible option for managing CUP with MPE mimicking gynecological malignancies with elevated Ca-125 and Ca 15-3 markers; initiating chemotherapy in poor performance status patients is beneficial with proper clinical judgment.