Background: Patients with advanced esophageal/gastroesophageal junction (GEJ) cancer have a dismal outcome. No study has unequivocally proven that systemic chemotherapy prolongs survival. Current NCCN guidelines recommend palliative/best supportive care as a first-line option for patients with unresectable locally advanced, recurrent, or metastatic esophageal/GEJ cancers. Methods: Phase III randomized controlled study conducted in the Department of Medical Oncology at the Tata Memorial Hospital (Mumbai, India) in patients with advanced unresectable or metastatic esophageal or GEJ cancer, planned for palliative intent therapy. Patients aged 18 to 70 years, with a performance status < 2, were stratified based on histopathology, presence of metastatic disease and receipt of prior curative therapy, and randomized 1:1 to best supportive care alone, or best supportive care with chemotherapy consisting of intravenous paclitaxel 80 mg/m² once-a-week, continued until disease progression or intolerable toxicity. Best supportive care consisted of patient education and counselling, non-chemotherapeutic palliative measures like radiation, or stenting, placement of feeding tube, analgesia, antiemesis and other supportive medications, nutritional support, and referral to a patient support group. Primary endpoint was overall survival (OS); secondary endpoints included progression free survival (PFS), response rate, adverse events, and quality of life. Results: Between May 2016 and Dec 2020, we recruited 281 patients; 143 to chemotherapy and 138 to best supportive care. Histopathology was squamous in 269 (95.7%) patients. In the 143 patients in the chemotherapy arm, median number of paclitaxel cycles was 12 (IQR, 7-23). The response rate was 32%. Grade > 3 toxicities occurred in 82 (57%) patients who received paclitaxel; commonly hyponatremia (18%), anemia (11%), fatigue (10%), peripheral neuropathy (10%), infection (9%), and neutropenia (7%). Median PFS was 2.1 months (95% CI, 1.98-2.23) in the best supportive care arm, and 4.1 months in the chemotherapy arm (95% CI, 3.54-4.74); HR, 0.51 (95% CI, 0.39-0.64); P < 0.001. The 1-year OS was 11.6% in the best supportive care arm, versus 30.8% in the chemotherapy arm. Median OS was 4.2 months (95% CI, 2.93-5.42) in the best supportive care arm, and 8.6 months in the chemotherapy arm (95% CI, 7.56-9.66); HR, 0.52 (95% CI, 0.40-0.66); P < 0.001. Conclusions: Systemic chemotherapy significantly prolongs survival and should be considered the standard of care in patients with advanced esophageal and GEJ squamous cell carcinoma. Metronomic weekly paclitaxel is an attractive option, especially in LMICs with limited access to newer immunotherapy-based combination regimens. Clinical trial information: CTRI/2016/01/006474.