Abstract Background The objective of this study was to investigate the association of polymorphisms in four genes, tumor necrosis factor-α (TNFA), patatin-like phospholipase domain containing 3 (PNPLA3), adiponectin (ADIPOQ) and apolipoprotein C3 (APOC3), with obesity and non-alcoholic fatty liver disease (NAFLD) in Asian Indian adolescents. Methods In this case-control study, 218 Asian Indian adolescents with overweight/obesity and 86 lean healthy adults without fatty liver were enrolled. Hepatic steatosis was assessed and graded by ultrasonography (USG). Serum insulin, lipids, alanine aminotransferase (ALT), aspartate aminotransferase (AST), TNF-α, adiponectin and apolipoprotein C3 were measured and genotyping was done. Frequencies of variant and wild genotypes in all adolescents and in the subgroups without steatosis, with grade 1 steatosis and with grade 2 or 3 steatosis were compared to those in the controls. The frequencies were also compared in the overweight adolescents with grade 2 or 3 steatosis and without steatosis. Results Variant genotypes of polymorphisms −863 C > A and −1031 T > C of the TNFA gene, 455 T > C of the APOC3 gene and the wild type of +276 G > T of the ADIPOQ gene were associated with obesity with odds ratios (OR, 95% confidence interval [CI]) of 2.5 (1.5–4.4), 2.5 (1.5–4.2), 2.0 (1.1–3.6) and 2.5 (1.4–5.0), respectively. Polymorphisms 455 T > C of APOC3 and rs738409 C > G of PNPLA3 were associated with NAFLD. Fasting insulin and triglycerides (TG) were higher in the adolescents with homozygous variant polymorphisms −1031 T > C of TNFA and 455 T > C of APOC3 genes, respectively. Conclusions Several polymorphisms were noted to have a significant association with obesity and NAFLD in Asian Indian adolescents.