Pistachios contain beneficial substances such as unsaturated fatty acids, phytosterols, and polyphenols. In the present study, we investigated if pistachio consumption is able to prevent or to revert hyperglycemia, dyslipidemia, hepatic steatosis, and adipose tissue morphological alterations caused by high fat diet (HFD) in the mouse. Moreover, the impact of pistachio intake on the mRNA expression of peroxisome proliferator-activated receptor γ ( ), fatty acid transport proteins ( ), fatty acid synthase ( ), stearoyl-CoA desaturase ( ), and sterol regulatory element-binding transcription factor-1c ( ) in liver and adipose tissue was also analyzed. No change in body weight, food intake, and hyperglycemia was observed between mice consuming pistachios (HFD-P) and HFD mice. Pistachio intake was able to prevent but not to reverse HFD-induced hypertriglyceridemia. Cholesterol plasma levels, steatosis grading, body fat mass, and adipocyte size were significantly lower in HFD-P group compared to HFD in both prevention and reversal protocol. Pistachio-diet was able to prevent HFD-induced overexpression of , , and in the liver and , and in adipose tissue. Similarly, HFD-P significantly ameliorated the expression levels of and in the liver and , and in adipose tissue of obese mice. The present study shows that pistachio consumption is able to prevent and to ameliorate obesity-related dysfunctions by positively modulating the expression of genes linked to lipid metabolism.