Cognitive impairment is common in patients with pain. While symptoms of pain are effectively treated with osteopathic manipulative treatment (OMT), the cognitive complaint is vastly ignored. Pain-induced cognitive dysfunction can be severe and is particularly apparent in working memory and attention. There is good reason to expect cognitive responsiveness to OMT. Previous research has reported the effects of OMT on related psychiatric outcomes, including relief from depression and anxiety, suggesting that OMT may produce more cortical benefits than is currently thought. The rationale to link OMT to cognition comes from the tenets of osteopathic medicine: body unity, homeostasis, and the structure-function relationship. The present article provides background evidence to support the hypothetical link between OMT and cognitive benefits and proposes a physiological mechanism of how OMT could exert its effect on cognition. Research strategies are discussed to test the hypotheses that are generated from the proposed theoretical framework.