A systematic review and meta-analyses were undertaken to investigate the association of SLC11A1 genetic variants with disease occurrence. Literature searching indentified 109 publications to include in the meta-analyses assessing the association of 11 SLC11A1 variants with autoimmune and infectious disease. The (GT) n promoter alleles 2 and 3 (rs534448891), which alter SLC11A1 expression, were significantly associated with tuberculosis (OR= 1.47 (1.30–1.66), OR= 0.76 (0.65–0.89), respectively) and infectious disease (OR= 1.25 (1.10–1.42), OR= 0.83 (0.74–0.93), respectively). However, although no association was observed with autoimmune disease, a modest significant association was observed with type 1 diabetes (allele 2 OR= 0.94 (0.89–0.98)). On the basis of a stronger association of (GT) n allele 2 with tuberculosis, compared with the protective effect of allele 3, we hypothesise that allele 2 is likely the disease-causing variant influencing disease susceptibility. Significant associations were observed between the 469+ 14G/C polymorphism (rs3731865) and autoimmune disease (OR= 1.30 (1.04–1.64)) and rheumatoid arthritis (OR= 1.60 (1.20–2.13)) and between the− 237C/T polymorphism (rs7573065) and inflammatory bowel disease (OR= 0.60 (0.43–0.84)). Further, significant associations were identified between the 469+ 14G/C, 1730G/A and 1729+ 55del4 polymorphisms (rs3731865, rs17235409 and rs17235416, respectively) and both infectious disease per se and tuberculosis. These findings show a clear association between variants in the SLC11A1 locus and autoimmune and infectious disease susceptibility.