Background <p>Gastric cancer (GC) is one of the most prevalent cancers worldwide, with high mortality and economic burden. Early detection through cost-effective screening strategies can improve patient outcomes and optimize healthcare resource allocation. This systematic review evaluates the cost-effectiveness of various GC screening approaches.</p> Methods <p>A comprehensive search was conducted in Web of Science, Scopus, PubMed, Embase, the NHS Economic Evaluation Database, and Google Scholar for studies published between 1990 and 2023. Relevant studies were selected based on predefined inclusion and exclusion criteria. The CHEERS 2022 checklist was used to assess study quality.</p> Results <p>A total of 6027 studies were retrieved, and after a two-phase screening and quality assessment, 47 studies were included. Most studies originated from China, Japan, the USA, Singapore, and South Korea. Findings indicate that screening is generally more cost-effective than no screening. Endoscopy was more cost-effective than upper gastrointestinal (UGI) X-ray but not superior to <i>Helicobacter pylori</i> (<i>H. pylori</i>) screening, serum pepsinogen (PG) testing, or novel risk scoring methods. <i>H. pylori</i> screening was more cost-effective than endoscopy and symptomatic treatment but not superior to serum PG testing and risk scoring methods. Urea breath test (UBT)-based <i>H. pylori</i> screening was less cost-effective than most alternatives.</p> Conclusions <p>Selecting cost-effective GC screening strategies can improve early detection rates and reduce healthcare costs. Policymakers should consider population-specific factors when implementing screening programs to maximize health benefits and economic efficiency.</p>