Single nucleotide polymorphisms (SNPs) in IRGM are reported to affect Mycobacterium tuberculosis (M.tb) degradation pathway. Here, we aim to screen promoter-region regulatory SNPs of IRGM in Pakistani population. DNA extracted from blood of cohort containing 70 TB patients (TB) and 30 controls subjects (Ctrl), was amplified for IRGM promoter region, followed by DNA sequencing. Group-specific variations were found in allelic frequencies at four loci. Allele T (p-value = 0.03) at −1161T/C, allele G (p-value = 0.027) at −1133G/A; allele C (p-value = 0.029) at −1049C/T; and allele G (p-value = 0.02) at −708G/A, showed higher associations with TB in our cohort. These SNPs display strong linkage disequilibrium (LD) in Pakistani population. Haplotype analysis showed a significant association of haplotype −1161T/−1133G/−1049C/−708G (p-value = 0.007) to TB. This 4-SNP haplotype also represents an expression quantitative trait locus (eQTL), associated with Crohn's disease and chronic inflammatory diseases. Our findings show that variants −1161T/C, −1133G/A, −1049C/T, and −708G/A are associated with IRGM expression and susceptibility to TB in a Pakistani population.