IntroductionAmong the increasing number of cancer cases, colorectal cancer (CRC) cases are rising globally. The association of zinc in the neoplastic process of CRC is a major research avenue, yet the published reports have not provided any definitive conclusion. ObjectivesWe examined the association between serum zinc levels and CRC to test the potential of zinc dysregulation as a CRC susceptibility factor. MethodsIn this systemic review and meta-analysis, we extensively searched EBSCOhost, EMBASE, Cochrane Library, ProQuest, PubMed/MEDLINE, Scopus, and Web of Science as well as manual screening by subject experts for studies reporting serum/plasma/blood zinc levels in CRC patients and control subjects till 27th August 2023. Based on a random effect model, we estimated the mean difference in serum/plasma/blood zinc levels between CRC cases and control subjects. Subgroup differences and publication bias were also investigated, along with a critical appraisal of included studies. ResultsEighteen studies with 8330 participants were included. The difference in serum zinc between CRC patients and control subjects was –5.01 µg/dl [95% CI: −21.76 to 11.74; p=0.56]. Omitting a highly influential outlier study, made this difference statistically significant at –13.28 µg/dl [95% CI: −20.66 to -5.90, p<0.01]. The difference between study effects could not be explained by the difference in analytical methods for zinc assessment, or type of blood samples. ConclusionCRC patients had lower serum zinc levels. Some factors, such as different tumor grades of CRC, adenomas, and colonic polyps need to be further considered for a more conclusive association between serum zinc levels and risk for CRC.