Spinal manipulation has been an effective intervention for the management of various musculoskeletal disorders. However, the mechanisms underlying the pain modulatory effects of spinal manipulation remain elusive. Although both biomechanical and neurophysiological phenomena have been thought to play a role in the observed clinical effects of spinal manipulation, a growing number of recent studies have indicated peripheral, spinal and supraspinal mechanisms of manipulation and suggested that the improved clinical outcomes are largely of neurophysiological origin. In this article, we reviewed the relevance of various neurophysiological theories with respect to the findings of mechanistic studies that demonstrated neural responses following spinal manipulation. This article also discussed whether these neural responses are associated with the possible neurophysiological mechanisms of spinal manipulation. The body of literature reviewed herein suggested some clear neurophysiological changes following spinal manipulation, which include neural plastic changes, alteration in motor neuron excitability, increase in cortical drive and many more. However, the clinical relevance of these changes in relation to the mechanisms that underlie the effectiveness of spinal manipulation is still unclear. In addition, there were some major methodological flaws in many of the reviewed studies. Future mechanistic studies should have an appropriate study design and methodology and should plan for a long-term follow-up in order to determine the clinical significance of the neural responses evoked following spinal manipulation.