Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic hepatic disease; nevertheless, no definitive diagnostic method exists yet, apart from invasive liver biopsy, and nor is there a specific approved treatment. Runt-related transcription factor 1 (RUNX1) plays a major role in angiogenesis and inflammation; however, its link with NAFLD is unclear as controversial results have been reported. Thus, the objective of this work was to determine the proteins involved in the molecular mechanisms between RUNX1 and NAFLD, by means of systems biology. First, a mathematical model that simulates NAFLD pathophysiology was generated by analyzing Anaxomics databases and reviewing available scientific literature. Artificial neural networks established NAFLD pathophysiological processes functionally related to RUNX1: hepatic insulin resistance, lipotoxicity, and hepatic injury-liver fibrosis. Our study indicated that RUNX1 might have a high relationship with hepatic injury-liver fibrosis, and a medium relationship with lipotoxicity and insulin resistance motives. Additionally, we found five RUNX1-regulated proteins with a direct involvement in NAFLD motives, which were NFκB1, NFκB2, TNF, ADIPOQ, and IL-6. In conclusion, we suggested a relationship between RUNX1 and NAFLD since RUNX1 seems to regulate NAFLD molecular pathways, posing it as a potential therapeutic target of NAFLD, although more studies in this field are needed.