Background: Manual therapy applications can also be used in the conservative treatment of patients with Glenohumeral Osteoarthritis (GHOA). Purpose: To compare the effectiveness of manual therapy plus exercise applications vs exercise alone in patients with GHOA. Study Design: A randomized controlled clinical trial. The trial was registered at ClinicalTrials.gov, number NCT03958227. Methods: Forty patients with GHOA were evaluated for treatment. The patients were randomly divided into two groups which were the exercise group and manual therapy plus exercise group. Both groups underwent a similar exercise program three times a week for 5 weeks. After drop outs (mean ± SD age, 60.1 ± 8.7 years; 22 female) 30 patients completed the study. Pain, range of motion, muscle strength, functionality, health-related quality of life were assessed with before and after 5 weeks of treatment. Patient satisfaction was assessed after treatment. Results: After treatment, a statistically significant improvements in pain, joint range of motion, muscle strength, functionality, and quality of life were observed in both groups (p < 0.05). Shoulder internal rotation (p = 0.03), (ES = 0.15) and external rotation (p = 0.04), (ES = 0.25) ROM, abduction, internal rotation and external rotation muscle strength (p = 0.01, p = 0.009, p = 0.03), (ES = 0.21, ES = 0.22, ES = 0.14) DASH (p = 0.005), (ES = 0.25) and ASES (p = 0.005), (ES = 0.24) and PCS-12 (p = 0.004), (ES = 0.25) scores were improved in favor of the manual therapy group between groups. Conclusions: Adding manual therapy to exercise programs in patients with Glenohumeral Osteoarthritis may be effective in reducing pain, increasing joint range of motion, muscle strength, functionality, and quality of life.