Safflomide (N-caffeoyltryptamine) is a phenolic amide with serotonin receptor antagonist and antioxidant activities. We investigated the potential effects of safflomide on the expression of adipokines in vitro and in vivo. Safflomide did not affect the expressions of TNF-α, IL-6, and MCP-1/CCL2 in hypertrophic 3T3-L1 cells but upregulated adiponectin mRNA 1-5-fold at concentrations between 1 and 20 μM (p < 0.05). Because safflomide is a non-selective 5-HT receptor antagonist and because the expression of 5-HT2A receptor is often inversely correlated to adiponectin expression, the potential effects of 5-HT receptor antagonist activity of safflomide on the expression of adiponectin was further investigated in 3T3-L1 cells. At the concentration of 10 μM, safflomide was able to increase adiponectin protein production in 3T3-L1 cells more than 4-fold (p < 0.05), which was greater than the 5-HT2A antagonist ketanserin. The upregulation was partially suppressed by treatment with 5-HT2A agonists (serotonin and α-Me-5-HT), suggesting that safflomide may upregulate adiponectin expression more than by blocking 5-HT2A receptors in 3T3-L1 cells. Likely, the upregulation was also attributed to the antioxidant activity of safflomide because two safflomide analogues (N-cinnamoyltryptamine and N-coumaroyltryptamine) with less antioxidant activity were not as potent as safflomide. Rats supplemented with safflomide (3 mg/day) in a high-fat diet showed a significant plasma adiponectin increase (more than 30%) with a significant reduction in body weight, visceral fat, and improved insulin resistance compared to non-supplemented rats, demonstrating the in vivo activity of safflomide. These data suggest that safflomide may have beneficial effects on obesity-related conditions, such as low adiponectin, visceral obesity, and insulin resistance.