Objectives: Obesity is a known strong risk factor for the onset of knee osteoarthritis and is often accompanied by dysregulated lipid metabolism with elevated levels of free fatty acids such as saturated fatty acids (SFAs). The purpose of this study was to determine how autophagy varies in chondrocytes in response to predominant SFAs such as lauric, myristic, palmitic, and stearic acids. Methods: Normal human articular cartilage chondrocytes and C28/I2 chondrocyte cell lines were stimulated with different SFAs in both the absence and presence of interleukin-1β to study the effects of SFA and inflammatory cytokines in mediating the activation of autophagy. The effects of rapamycin and LY290042 on autophagy in response to different SFAs were also assessed. Results: Palmitic and stearic acid stimulation of chondrocytes resulted in increased activation of both autophagy and the canonical NFκB pathway as evidenced by increased expressions of the key autophagy markers microtubule-associated protein-1 light chain 3, autophagy-related 5, beclin-1, and NFκB p65. In contrast, lauric acid stimulation resulted in decreased autophagy activation as shown by decreased expressions of microtubule-associated protein-1 light chain 3, autophagy-related 5, and beclin-1, which suggests decreased cellular stress. Conclusions: These results represent a novel mechanism by which various SFAs activate autophagy and simultaneously modulate NFκB signaling pathways and the expression of chondrocyte regulatory genes.