Central sensitization (CS) is characterized by adaptations to the central nervous system resulting in decreased sensory thresholds and widespread hypersensitivity. CS is often difficult to manage, with current treatment strategies primarily consisting of medication, pain science education, cognitive behavioral therapy, and graded exercise intervention. Spinal manipulation represents a potential alternative treatment for CS because of its centrally acting neurophysiological mechanisms. However, experimental trials utilizing spinal manipulation in persons with CS often lack the controls or methodology required to determine the technique's effect on meaningful clinical outcomes. This paper summarizes the mechanistic and experimental evidence on spinal manipulation for centrally mediated pain and hypersensitivity, and offers recommendations for future study considerations in this topic area.