The aim of this study was to compare the effectiveness of arthrocentesis followed by hyaluronic acid infiltration treatment (ASH) and mandibular exercise therapy (MET) in patients with symptomatic disc displacement without reduction (DDwoR) by examining pain intensity (VAS), mandibular range of motion (MO), and quality of life (QoL). Fifty-two patients were randomly allocated into two groups, MET (N = 26) and ASH (N = 26), and therapy was applied at the baseline and one month after. Patients were followed up at 1 and 12 months after the baseline assessment. Clinical and patient-reported outcomes were compared at the baseline, 1-month follow-up, and 12-month follow-up. The study found no significant differences in VAS and MO between the ASH and MET groups at the baseline. However, while not significant, it was noted that the ASH group showed higher values for MO. Regarding OHIP-14 at 1 month of follow-up, the ASH group showed significant improvements in physical pain (p> 0.01), physical and psychological disability (p= 0.043 andp= 0.029), and handicap (p= 0.033). At the 12-month follow-up, the ASH group showed significant improvements in functional limitation, psychological discomfort, psychological disability, and handicap (p= 0.008,p= 0.001,p= 0.001,p= 0.005, respectively). ASH treatment did not reduce pain or improve mandibular range of motion more than physical therapy in patients with symptomatic DDwoR. However, ASH could be preferable given its positive long-term effects on patients’ quality of life. The clinician’s main objective is to prioritize the treatment plan order with a focus on the patient’s quality of life. Accordingly, healthcare professionals should consider ASH as a treatment option for patients with symptomatic DDwoR who desire long-term improvement in their quality of life.