Background: Fatigue is a common and debilitating non-motor symptom (NMS) in Parkinson’s disease (PD), significantly affecting patients’ quality of life. MAO-B inhibitors are effective therapy for motor symptoms and fluctuations and may also play a role in fatigue management. Methods: We searched PubMed for English-language articles (January 1978–August 2024) using keywords including “selegiline”, “rasagiline”, “safinamide”, “MAO-B”, “fatigue”, and “Parkinson’s disease”. Clinical trials, observational, and preclinical studies were included. Results: While the role of MAO-B inhibitors in fatigue remains unclear, evidence suggests potential benefits. Selegiline has shown effectiveness in improving fatigue in animal models, supporting its potential utility in treating fatigue and motivational impairments in PD patients. Rasagiline has been associated with reduced fatigue progression in early PD, with some studies showing significant improvements compared to placebo. Safinamide, with its dual action as an MAO-B inhibitor and glutamate modulator, may further enhance fatigue management. Its ability to reduce glutamate release is particularly relevant, given the role of glutamate overactivity in PD-related fatigue. Studies indicate safinamide can significantly reduce fatigue levels. Conclusions: Fatigue in PD is a complex symptom with multiple contributing factors. While MAO-B inhibitors may support fatigue management, their precise role and optimal use require further investigation.