Background and purpose Esophageal cancer has the seventh highest incidence and sixth highest fatality rate of all malignant tumors. It's a type of cancer that has a greater fatality rate than morbidity. In the treatment of advanced esophageal and squamous cell carcinoma, targeted and immune checkpoint inhibitors have showed promising outcomes in recent years. The aim of this research was to examine the effectiveness and safety of immune checkpoint inhibitors in combination with antiangiogenic medicines in the treatment of unresectable patients with locally progressed / distant metastatic esophageal squamous cell carcinoma. Methods Before April 15, 2022, randomized controlled trials of immune checkpoint inhibitors combined with anti-angiogenic drugs in the treatment of esophageal cancer will be searched on PubMed, Cochrane Library, EMBASE, WebofScience, China Knowledge Network, Wanfang Data Knowledge Service Platform, and VIP. The two authors independently extracted the data, checked the data, and used the "bias risk" tool in the Cochrane intervention system evaluation manual to independently evaluate the bias included in the study. When the extracted data were similar enough, the Revman5.4 software was used for meta analysis. If the summary data could not be collected for meta analysis, the results would be summarized in a narrative way. Discussion This paper introduces in detail the systematic review and design method of immune checkpoint inhibitors mixture with antiangiogenic drugs in the treatment of unresectable locally advanced / distant metastatic esophageal squamous cell carcinoma.