Background: This study aimed to investigate the effect of manual therapy on pain, kinesiophobia, pain catastrophizing, anxiety, depression, and quality of life in patients with lumbar disc herniation (LDH). Methods: The study included 32 LDH patients. Patients were divided into the Manual therapy group (MTG—age 39.81 ± 9.45 years) and the Exercise group (EG—age 38.31 ± 9.21 years) by sealed envelope randomization. Patients were evaluated pre-study, post-study, and after a 3-month period using the McGill–Melzack Pain Questionnaire (MMPQ), Hospital Anxiety and Depression Scale (HADS), Tampa Kinesiophobia Scale (TKS), Pain Catastrophizing Scale (PCS) and Nottingham Health Profile (NSP). The exercise group received a total of ten sessions of stabilization exercises and sham spinal mobilization in five weeks, two sessions per week. In addition to the stabilization exercises, mobilization applications including Anterior-Posterior Lumbar Spinal Mobilization, Lumbar Spinal Rotational Mobilization, and Joint Mobilization in Lumbar Flexion Position, were applied to the manual therapy group. Results: It was found that the HADS and TKS values decreased in the MTG group compared to the pre-treatment period (p < 0.05), while there was no difference between these values in the EG group (p > 0.05). There was a statistically significant difference in the MMPQ, PCS, and NHP values after treatment in both the MTG and EG groups (p < 0.05). Conclusions: It was found that manual therapy had positive effects on psychological factors such as pain, kinesiophobia, pain catastrophizing, anxiety, depression, and quality of life in patients with LDH. Trial registration: NCT05804357 (27 March 2023) (retrospectively registered).