Significant changes in human lifestyle have occurred in the past century, leading to a substantial increase in obesity. This has led to the rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), affecting approximately 25% of the world population predicted to surge 30% by 2030. MASLD currently has no approved pharmacotherapy. Left untreated, MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis and primary liver cancer. We therefore studied whether pharmacological modulation of peroxisome proliferator-activated receptor alpha (PPARα) and estrogen-related receptor (ERRα) in tandem may interfere with MASLD progression. Using a short-term MASLD mice model, 8-week-old male mice were fed a Western diet + fructose water for 2 weeks. After one week, they were administered daily oral gavage for 7 days with PPARα agonist Pemafibrate (0.1 mg/kg) and/or ERRα inverse agonist C29 (30 mg/kg). The liver samples were subjected to histological evaluation, qPCR and RNA sequencing. Using a long-term MASLD mice model, western diet + fructose was fed to male mice for 16 weeks and daily oral gavage was administered (week 10 to week 16).  Clinical effects, blood parameters, morphological/histological and gene expression of the liver were evaluated. The RNA sequencing results clearly showed distinct clusters of genes and significantly affected more genes with the combination treatment. This was also observed via qPCR. The livers in the long-term MASLD mice model appeared visually healthier with the ligand combination. Steatosis, ballooning, inflammation, MASLD activity score, fibrosis, and ORO were also significantly improved.  Scanning electron microscopy further confirmed the significant decrease in steatosis and fibrosis with the combination treatment. Furthermore, the ligand combination improved gene expression involved in lipid metabolism, inflammation and fibrosis markers.  This confirms PPARα -ERRα is a viable novel strategy against MASLD.