Background Although neoadjuvant chemotherapy and immunotherapy show promise in treating oesophageal squamous cell carcinoma (OSCC), long-term survival data are limited. This randomized, multicenter phase 2 study evaluated the efficacy of perioperative Nivolumab with chemotherapy, followed by surgery and adjuvant immunotherapy, in patients with locally advanced resectable OSCC, and explored the prognostic role of circulating tumor DNA (ctDNA) status. Methods In this trial, participants recruited from five centers were randomly assigned in a 2:1 ratio to receive either perioperative Nivolumab or a placebo in addition to chemotherapy (cisplatin and paclitaxel), followed by minimally invasive esophagectomy. For those who did not achieve a pathological complete response (pCR), adjuvant treatment with Nivolumab was administered. The main measure of success was the pCR rate, with secondary endpoints including the R0 resection rate, event-free survival, and overall survival. All outcomes and safety measures were assessed based on the intention-to-treat population. ctDNA levels were monitored as exploratory endpoints. Results Ninety patients were enrolled and randomized to Nivolumab or placebo plus chemotherapy. The pCR rate was slightly higher in the Nivolumab group (15%) compared to the control group (13.3%) (relative risk, 1.13; 95% CI, 0.38 to 3.36). No significant differences were observed in R0 resection rates (96.4% vs. 96.6%; P > 0.05). The median follow-up duration was 24.9 months (interquartile range: 22.8 to 26.7 months). Two-year event-free survival rates were 63.11% in the Nivolumab group versus 60.47% in the chemo group (hazard ratio, 0.97; 95% CI, 0.49 to 1.92). Two-year overall survival rates were 83.32% and 79.4%, respectively (hazard ratio, 0.82; 95% CI, 0.29 to 2.31). All participants were ctDNA positive at baseline, but post-treatment, 89% of the Nivolumab group and 62.5% of the placebo group turned ctDNA negative (P = 0.01). Those negative for ctDNA at all testing points showed significantly better disease-free survival (P < 0.001). Conclusions Perioperative Nivolumab plus chemotherapy is a viable and safe option for systemically treating locally advanced resectable OSCC. Monitoring minimal residual disease through ctDNA could be potentially valuable for assessing the effectiveness of adjuvant therapy and for prognostic evaluation in a systemic manner.