Background Knee osteoarthritis is a highly prevalent disease worldwide that leads to functional disability and chronic pain. It has been shown that not only changes are generated at the joint level in these individuals, but also neuroplastic changes are produced in different brain areas, especially in those areas related to pain perception, therefore, the objective of this research was to identify and compare the structural and functional brain changes in knee OA versus healthy subjects. Methodology Searches in MEDLINE (PubMed), EMBASE, WOS, CINAHL, SCOPUS, Health Source, and Epistemonikos databases were conducted to explore the available evidence on the structural and functional brain changes occurring in people with knee OA. Data were recorded on study characteristics, participant characteristics, and brain assessment techniques. The methodological quality of the studies was analysed with Newcastle Ottawa Scale. Results Sixteen studies met the inclusion criteria. A decrease volume of the gray matter in the insular region, parietal lobe, cingulate cortex, hippocampus, visual cortex, temporal lobe, prefrontal cortex, and basal ganglia was found in people with knee OA. However, the opposite occurred in the frontal lobe, nucleus accumbens, amygdala region and somatosensory cortex, where an increase in the gray matter volume was evidenced. Moreover, a decreased connectivity to the frontal lobe from the insula, cingulate cortex, parietal, and temporal areas, and an increase in connectivity from the insula to the prefrontal cortex, subcallosal area, and temporal lobe was shown. Conclusion All these findings are suggestive of neuroplastic changes affecting the pain matrix in people with knee OA.