Reduced plasma levels of the high-molecular weight (HMW) form of adiponectin, rather than total adiponectin levels, have been shown to be closely associated with various metabolic diseases including insulin resistance, type 2 diabetes, and cardiovascular disease. Therefore, we sought to explore active, naturally occurring compounds that promote the recovery of HMW adiponectin secretion suppressed by palmitic acid in our model. A total of 90 crude drug extracts were screened for the ability to augment HMW adiponectin secretion from 3T3-L1 adipocytes treated with palmitic acid. Panaxynol was isolated from Saposhnikovia divaricata as an active compound with HMW adiponectin promoting properties. Peroxisome proliferator-activated receptor-γ (PPARγ) agonists are reported to increase the secretion of HMW adiponectin, although the effects of panaxynol were found to be independent of PPARγ activation. When the underlying mechanisms were further examined, panaxynol was found to inhibit the palmitic-acid-induced downregulation of forkhead box O1 (FoxO1) protein, and the anti-lipotoxic effects were abolished by a FoxO1 inhibitor. Furthermore, CCAAT/enhancer-binding protein-α (C/EBPα) mRNA levels were also increased by panaxynol. Reactive oxygen species have critical roles in the reduction in HMW adiponection secretion by palmitic acid; however, panaxynol reduced this increase in reactive oxygen species generation, followed by reductions in markers of endoplasmic reticulum stress and inflammation. Taken together, these findings suggest that panaxynol ameliorates the impaired HMW adiponection secretion in adipocytes treated with palmitic acid by restoring FoxO1 expression, owing to inhibition of reactive oxygen species generation, in a PPARγ-independent manner.