Referred sensation (RS) as a specific clinical phenomenon has been known for a long time, although the underlying mechanisms remain unclear. The aims of this study were to assess if (1) healthy individuals who experienced RS had a less active endogenous pain system when compared with those who did not; (2) activation of descending pain inhibition mechanisms can modulate RS parameters; and finally, (3) a transient decrease in peripheral afferent input because of a local anesthetic (LA) block in the masseter muscle can modulate RS parameters. To assess these, 50 healthy participants were assessed in 3 different sessions. In the first session, conditioned pain modulation (CPM) as well as mechanical sensitivity and RS at the masseter muscle were assessed. In the same session, participants who experienced RS had their mechanical sensitivity and RS assessed again while undergoing a CPM protocol. In the second and third sessions, participants had their mechanical sensitivity and RS assessed before and after receiving an injection of 2 mL of LA and isotonic saline into the masseter muscle. The main findings of this study were (1) participants who experienced RS during standardized palpation exhibited increased mechanical sensitivity (P < 0.05, Tukey post hoc test) and decreased CPM (P < 0.05, Tukey post hoc test) when compared with those who did not; RS incidence (P < 0.05, Cochran Q test), frequency (P < 0.05; Friedman test), intensity (P < 0.05, Tukey post hoc test), and area (P < 0.05, Tukey post hoc test) were all significantly reduced when assessed (2) during a painful conditioning stimulus and (3) after LA block. These novel findings highlight that RS in the orofacial region are strongly modified by both peripheral and central nervous system factors.