Some phytochemicals and micronutrients may directly scavenge free radicals or they may modulate expression of antioxidant genes. Alternatively, they may modulate lipid metabolic genes in tissues and reduce plasma lipid levels and thus indirectly prevent lipid‐mediated oxidative and endoplasmatic stress. Here we analyzed the molecular mechanisms by which the polyphenol curcumin may influence the elevated oxidative‐ and lipid‐mediated stress present during inflammation, obesity and atherosclerosis. In LDLr−/−mice fed a high fat diet (HFD), we found that curcumin (500, 1000, 1500 mg/kg diet, for 4 months) reduced plasma lipid levels what may indirectly contribute to inhibition of fatty acid transport proteins (CD36/FAT, FABP4/aP2) in peritoneal macrophages. Curcumin increased the HFD‐induced suppressed cAMP levels in tissues (liver, adipose). In THP‐1 monocytes, curcumin (5 and 10 μM) increased the level of cAMP and activated the transcription factor CREB. Since the cAMP/protein kinase A (PKA)/CREB pathway plays an important role in lipid homeostasis, energy expenditure and thermogenesis by increasing lipolysis and fatty acid β‐oxidation, an increase in cAMP levels induced by curcumin could be at the basis of its hypolipidemic and anti‐atherosclerotic effects, and similar to forskolin or caffeine also explain its effect on suppressing weight gain. Supported by USDA Contract #58–1950‐0–014.