Background <p>Colorectal cancer (CRC) is the third most common cancer globally, with rising cases in Latin America. MSI-H and MMRd play key roles in CRC, but data on their prevalence in Hispanic/Latino populations are limited. This study evaluates these biomarkers in the region.</p> Methods <p>A systematic review and meta-analysis were conducted following PRISMA guidelinesin Medline, Virtual Health Library, Scopus, and Web of Science. Random-effects models were used to estimate pooled prevalence due to expected heterogeneity between studies. Studies (cohort and cross-sectional) that evaluated MMRd and/or MSI-H through IHC and PCR techniques in Hispanic/Latino individuals with colorectal cancer (whether sporadic, associated with Lynch Syndrome, or other forms), residing in Latin American countries or elsewhere, were included.</p> Results <p>A total of 52 studies including 10,596 patients were included. The pooled prevalence of mismatch repair deficiency (MMRd) and microsatellite instability-high (MSI-H) in Hispanic/Latino populations was 15% (95% CI: 10%–20%; I² = 89.6%) and 18% (95% CI: 13%–24%; I² = 84.0%), respectively. Costa Rica and Mexico had the highest MMRd prevalence (30% and 24%), while Uruguay showed the highest MSI-H prevalence (45%). MSI-H was significantly associated with female sex (OR: 1.83) and right-sided tumors (OR: 8.16). MMRd was associated with right-sided tumors compared with the rectum (OR: 1.73) and the left colon (OR: 5.65).</p> Conclusions <p>This meta-analysis underscores the unique prevalence of MMRd and MSI-H in Hispanics, highlighting regional variations and the need for broader representation.</p>