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Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis in western countries. Insulin resistance (IR), type 2 diabetes (T2D), and the polymorphisms patatin-like phospholipase domain-containing 3 (<i>PNPLA3</i>) rs738409 and transmembrane 6 superfamily member 2 (<i>TM6SF2</i>) rs58542926 are independent risk factors of NASH. Nevertheless, little is known about the interaction between IR and T2D with these polymorphisms in the pathogenesis of NASH and the development of advanced fibrosis. Thus, our study aimed to investigate this relationship. This is a cross-sectional study including NASH patients diagnosed by liver biopsy, at the Vall d’Hebron University Hospital. A total of 140 patients were included (93 T2D, 47 non-T2D). T2D (OR = 4.67; 95%CI 2.13–10.20; <i>p</i> < 0.001), <i>PNPLA3</i> rs738409 and <i>TM6SF2</i> rs58542926 polymorphisms (OR = 3.94; 95%CI 1.63–9.54; <i>p</i> = 0.002) were independently related with advanced liver fibrosis. T2D increased the risk of advance fibrosis on top of the two polymorphisms (OR = 14.69; 95%CI 3.03–77.35; <i>p</i> = 0.001 for <i>PNPLA3</i> rs738409 and OR = 11.45; 95%CI 3.16–41.55; <i>p</i> < 0.001 for <i>TM6SF2</i> rs58542926). In non-T2D patients, the IR (HOMA-IR ≥ 5.2, OR = 14.33; 95%CI 2.14–18.66; <i>p</i> = 0.014) increased the risk of advanced fibrosis when the polymorphisms were present (OR = 19.04; 95%CI 1.71–650.84; <i>p</i> = 0.042). The T2D and IR status increase the risk of advanced fibrosis in patients with NASH carrying the <i>PNPLA3</i> rs738409 and/or <i>TM6SF2</i> rs58542926 polymorphisms, respectively.