Non-alcoholic fatty liver disease (NAFLD) has emerged pandemically across the globe and particularly affects patients with obesity and type 2 diabetes. NAFLD is a complex systemic disease that is characterised by hepatic lipid accumulation, lipotoxicity, insulin resistance, gut dysbiosis and inflammation. In this review, we discuss how metabolic dysregulation, the gut microbiome, innate and adaptive immunity and their interplay contribute to NAFLD pathology. Lipotoxicity has been shown to instigate liver injury, inflammation and insulin resistance. Synchronous metabolic dysfunction, obesity and related nutritional perturbation may alter the gut microbiome, in turn fuelling hepatic and systemic inflammation by direct activation of innate and adaptive immune responses. We review evidence suggesting that, collectively, these unresolved exogenous and endogenous cues drive liver injury, culminating in liver fibrosis and advanced sequelae of this disorder such as liver cirrhosis and hepatocellular carcinoma. Understanding NAFLD as a complex interplay between metabolism, gut microbiota and the immune response will challenge the clinical perception of NAFLD and open new therapeutic avenues.