Background: The correlation between fatigue and disability in multiple sclerosis (MS) with the hypothalamus-pituitary-adrenal axis is known. This study aimed to investigate the relationship between the morphometric dimensions of the pituitary gland with fatigue and disability. Method: This research, designed as a prospective and case-control study, included 85 MS patients and 45 healthy controls. The disability was evaluated using the expanded disability rating scale (EDSS), while fatigue was determined using the fatigue severity scale (FSS) and the neurological fatigue index (NFI-MS). The morphometric structure of the pituitary gland was measured using a coronal, T2-weighted, turbo-spin-echo sequence of magnetic resonance imaging. Results: FSS and NFI-MS scores were higher in MS patients than in the control group (p = 0.001). Patients with a progressive and moderate-to-severe disability had a higher FSS score (p = 0.015; p = 0.002, respectively). A positive correlation was determined between disease duration, attack frequency, and EDSS and physical fatigue subscale score (p = 0.001; r = 0.383; 0.373; 0.545, respectively). The height and width of the pituitary gland were higher in MS patients (p = 0.021; p = 0.001, respectively). Pituitary gland height was higher in fatigued patients (p = 0.041). A low-positive correlation was determined between the number of attacks and the height of the pituitary gland (p = 0.027, r = 0.231). Conclusion: The difference in the dimensions of the pituitary gland in MS patients, especially in the fatigued group, supports the relationship of fatigue with morphometric features as well as the hypothalamus-pituitary-adrenal axis.