FAM3C is a member of the family with sequence similarity 3 (FAM3) gene family, and this study determined its role and mechanism in regulation of hepatic glucose/lipid metabolism. In obese diabetic mice, FAM3C expression was reduced in the liver, and hepatic FAM3C restoration improved insulin resistance, hyperglycemia, and fatty liver. FAM3C overexpression increased the expression of heat shock factor 1 (HSF1), calmodulin (CaM), and phosphorylated protein kinase B (Akt) and reduced that of gluconeogenic and lipogenic genes in diabetic mouse livers with the suppression of gluconeogenesis and lipid deposition. In cultured hepatocytes, FAM3C overexpression upregulated HSF1 expression, which elevated CaM protein level by inducing CALM1 transcription to activate Akt in a Ca2+- and insulin-independent manner. Furthermore, FAM3C overexpression promoted nuclear exclusion of FOXO1 and repressed gluconeogenic gene expression and gluconeogenesis in a CaM-dependent manner in hepatocytes. Hepatic HSF1 overexpression activated the CaM-Akt pathway to repress gluconeogenic and lipogenic gene expression and improve hyperglycemia and fatty liver in obese diabetic mice. In conclusion, the FAM3C-HSF1-CaM-Akt pathway plays important roles in regulating glucose and lipid metabolism in hepatocytes independent of insulin and calcium. Restoring hepatic FAM3C expression is beneficial for the management of type 2 diabetes and fatty liver.