PGC-1α (Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) plays a key role in glucose homeostasis inside liver and muscle. The impact of six polymorphisms of PGC-1α with Type 2 Diabetes (T2D) susceptibility was evaluated on 1125 samples comprising of 554 T2D cases and 571 controls among three endogamous groups (Bania, Brahmin and Jat Sikh) of North-West India (Punjab). Single-locus analysis showed a significant differential pattern of genetic association of PGC-1α among studied groups emphasizing the role of ethnicity towards disease susceptibility. Haplotypes G-A-G-G-C-C in Bania group; G-G-G-G-C-A in Brahmin; G-A-A-G-T-C, G-G-G-G-T-C in Jat Sikh groups conferred ~ two to fivefold increased T2D risk. Intriguingly, the haplotype combination G-A-G-G-C-C provided T2D risk in Banias whereas it played a protective role in Brahmins reflecting the role of ethnic heterogeneity. In the secondary structure prediction of mRNA, slight free energy change along with structural changes was observed between the wild and variant allele of rs3736265, rs8192678 and rs2970847 loci. Meta-analyses conducted on rs8192678 and rs2970847 variants illustrated the overall effect of minor alleles providing a higher risk for the T2D development. Divergence in genetic variants and haplotype combinations associated with T2D risk among studied groups is inferred from the present dataset, which strongly highlights the combinatorial effect of diverse ethnic background of the population under study with genetics towards susceptibility to complex diseases like T2D.