Introduction Non‐alcoholic fatty liver disease (NAFLD) disproportionately affects Hispanic/Latinos and rates of NAFLD vary among Hispanics from different background groups. Genetic variants and continental ancestry contribute to NAFLD disparities among Hispanics. We evaluated two newly identified NAFLD‐associated single nucleotide polymorphisms of HSD17B13, rs72613567:TA and rs62305723:A in Hispanics/Latinos. Methods Clinical data, genotypes of variants of interest and estimates of continental ancestry were extracted from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) database, which includes a cohort of 16 415 US Hispanic/Latinos. Surrogate endpoints for NAFLD were suspected NAFLD based on unexplained aminotransferase elevation, continuous ALT levels and FIB‐4 scores to estimate hepatic fibrosis. Results In all, 9342 participants were included for analysis. The rs72613567:TA allele was found in 15.3% and the rs62305723:A allele was identified in 4.5% of HCHS/SOL participants. rs72613567:TA was less frequent in persons with vs without suspected NAFLD (12.4% vs 15.7%, P < .001) and rs72613567:TA was associated with lower FIB‐4 scores (P = .01). For persons with the NAFLD‐associated PNPLA3 rs738409:G allele, the presence of rs72613567:TA was associated with a lower rate of suspected NAFD (odds ratio = 0.76, P < .001). rs72613567:TA was less frequent in Hispanic/Latino background groups with higher rates of suspected NAFLD. The rs62305723:A allele was not associated with suspected NAFLD or FIB‐4 score. Conclusion The rs72613567:TA allele is associated with lower rates of suspected NAFLD and lower FIB‐4 scores among Hispanic/Latinos and with lower rates of suspected NAFLD in persons with the PNPLA3 rs738409:G allele. The rs72613567:TA allele contributes to NAFLD disparities among Hispanic/Latino background groups. See Editorial on Page 756