Non-alcoholic fatty liver disease (NAFLD), attributed to excessive fat accumulation in the liver, is reportedly prevalent worldwide. NAFLD is one of the leading causes of chronic liver disease, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatic cellular carcinoma (HCC). The peripheral roles of serotonin (5-hydroxytryptamine, 5HT) were found to regulate hepatic lipid metabolism. Among serotonin receptor subtypes, 5HT(2A) receptor is known to regulate hepatic lipid metabolism. Hepatic lipid accumulation and hepatic triglyceride (TG) were reduced in liver-specific 5HT(2A) receptor knockout (5HT(2A) receptor LKO) mice upon high-fat diet (HFD) feeding. In the present study, we explored a series of new peripherally acting 5HT(2A) receptor antagonists. Compound 14a displayed good in vitro activity, with an IC50 value of 0.17 nM. Compound 14a exhibited good microsomal stability, no significant CYP and hERG inhibition, and 5HT receptor subtype selectivity. The brain-to-plasma ratio of 14a was below the lower limit of quantification, indicating limited blood-brain barrier (BBB) penetration. HFD-fed 14a treated mice showed decreased liver steatosis and lobular inflammation. These results demonstrate the potential of newly synthesized peripheral 5HT(2A) receptor antagonists for treating NAFLD.