Upregulation of defensive reflexes such as the nociceptive flexion reflex (NFR) has been attributed to sensitisation of peripheral and spinal nociceptors and is often considered biomarkers of pain. Experimental modulation of defensive reflexes raises the possibility that they might be better conceptualised as markers of descending cognitive control. Despite strongly held views on both sides and several narrative reviews, there has been no attempt to evaluate the evidence in a systematic manner. We undertook a meta-analytical systematic review of the extant English-language literature from inception. Thirty-six studies satisfied our a priori criteria. Seventeen were included in the meta-analysis. Reflexive threshold was lower in people with clinical pain than it was in pain-free controls, but reflex size, latency, and duration were unaffected. The pattern of difference was not consistent with sensitisation of nociceptive neurones, as these changes were not isolated to the affected body part but was more consistent with top-down cognitive control reflective of heightened protection of body tissue. The pattern of modulation is dependent on potentially complex evaluative mechanisms. We offer recommendations for future investigations and suggest that defensive reflex threshold may reflect a biomarker of a broader psychological construct related to bodily protection, rather than sensitisation of primary nociceptors, spinal nociceptors, or pain.