The objective was to compile, synthetize, and evaluate the quality of the evidence from randomized controlled trials (RCTs) regarding the effectiveness of manual trigger point therapy in the orofacial area in patients with or without orofacial pain. This project was registered in PROSPERO and follows the PRISMA guidelines. Searches (20 April 2021) were conducted in six databases for RCTs involving adults with active or latent myofascial trigger points (mTrPs) in the orofacial area. The data were extracted by two independent assessors. Four studies were included. According to the GRADE approach, the overall quality/certainty of the evidence was very low due to the high risk of bias of the studies included. Manual trigger point therapy showed no clear advantage over other conservative treatments. However, it was found to be an equally effective and safe therapy for individuals with myofascial trigger points in the orofacial region and better than control groups. This systematic review revealed a limited number of RCTs conducted with patients with mTrPs in the orofacial area and the methodological limitations of those RCTs. Rigorous, well-designed RCTs are still needed in this field.