Considerable evidence suggests that knee osteoarthritis (OA)-related clinical pain and disability significantly differs according to racial background. However, brain mechanisms underlying these differences are not well understood. We investigated altered central pain processing in a sample comprised of Non-Hispanic Black (NHB) and Non-Hispanic White (NHW) adults with and without knee OA. NHB and NHW participants with knee OA (n = 123) and without knee OA (N = 41) were recruited to complete a brain imaging protocol using Arterial Spin Labeling (ASL) on a 3T fMRI scanner. Participant's regional cerebral blood flow (rCBF), a measure of brain activation, was examined at rest and during pressure pain stimulation. Aim 1 was to examine altered central processing in people with knee OA compared to people without knee OA. Aim 2 assessed racial group differences in central processing among NHB and NHW adults with knee OA. People with knee OA showed significant differences in rCBF at rest and during pain in the anterior cingulate cortex, sensory-motor cortex, para-hippocampal gyrus, and amygdala in comparison to people without knee OA. For people with knee OA, ethnic differences between NHWs (n = 52) and NHBs (n = 71) were present in the cingulate gyrus, amygdala, thalamus, sensory-motor cortex, and cerebellum. Comparing people with knee OA to people without knee OA at rest while controlling for race, we found a significant effect in the thalamus (p = .036) and amygdala (p = .046). For people with knee OA, NHBs vs NHWs showed a significant effect for the difference score (pain - rest) in the cerebellum (p = .012) when controlling for age and education. These results indicate that knee OA and racial background may be important contributors to altered central nervous system processing of pain. Supported in part by NIH/NIA grant AG033906 and the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Alabama at Birmingham (ULITR000165).