Background: Myofascial pain of the masticatory muscles significantly contributes to temporomandibular disorders (TMD) and is often associated with impaired function and depressive symptoms. While trigger point injections like dry needling and local anesthetics are common, direct comparisons in the orofacial region are limited. This randomized trial compared the effectiveness of dry needling, lidocaine, and mepivacaine regarding myofascial pain, self-reported TMD symptoms, and depressive symptoms. Methods: In this double-blind trial, 75 patients with bilateral active masseter and temporalis trigger points were randomized to dry needling, lidocaine (20 mg/mL), or mepivacaine (30 mg/mL) ( n = 25 each). Interventions were administered weekly for three sessions. Pain intensity (Visual Analog Scale), depressive symptoms (Beck Depression Inventory), and TMD symptoms (Fonseca Anamnestic Index) were assessed at baseline and at a short-term follow-up (one week post-treatment). Two-way repeated measures ANOVA with Bonferroni post-hoc tests evaluated interactions between time and treatment. Results: All interventions significantly reduced pain, depressive, and TMD scores ( p < 0.001). A significant time x group interaction was observed for pain intensity ( p < 0.001). Mepivacaine achieved the greatest mean pain reduction (5.36), which was significantly superior to dry needling ( p = 0.001), whereas no significant difference was found between lidocaine and dry needling ( p = 0.226). No significant between-group differences were observed for changes in depressive or TMD symptom scores ( p > 0.05). Conclusions: All three modalities effectively reduced myofascial pain and improved psychological outcomes within the short-term observation period of one week. Mepivacaine demonstrated superior short-term pain reduction compared to dry needling. Both local anesthetics represent viable options for short-term myofascial pain management, though studies with longer follow-up periods are required to evaluate sustained effects and comparative advantages. Trial registration: ClinicalTrials.gov, NCT07079449. Registered on July 14, 2025.