Joint visco-supplementation is an effective therapeutic approach against the degenerative signs and symptoms of osteoarthrosis/osteoarthritis of the mandibular condyle. Supplements of choice are usually delivered inside the temporomandibular joint (TMJ) by intra-articular infiltration. The present study aimed to assess the clinical effectiveness of pericapsular injection of polinucleotides (PN) and hyaluronic acid (HA). Sixty patients suffering from TMJ osteoarthrosis were recruited and divided into two groups (test group: n = 30, pericapsular injection; control group: n = 30, self-delivered physiotherapeutic exercises). For each patient, maximum opening, right and left lateral excursion, and visual analogue scale (VAS) scores were recorded at four different timepoints by a blinded investigator. Paired Student’s t tests were used to compare consecutive measurements of the parameters evaluated within the groups, and unpaired Student’s t tests were used for between-group comparisons. All investigated parameters displayed a progressive clinical improvement in both groups, which was more accentuated in the test group. The decrease in VAS score differed significantly between groups (p < 0.0001). Maximum opening showed a continuous increase from baseline (mean (SD) 37.70 (8.33) mm) to T3 (39.68 (7.64) mm), reflecting a progressive improvement, but it was not statistically significant (p = 0.089 at T3 with respect to T0). PN HA pericapsular injection is a minimally invasive treatment that effectively reduces pain and improves mandibular kinematics.