Background: Parkinson’s disease (PD) is a common neurodegenerative disease associated with progressive gray matter atrophy. In addition to motor function disorder, frailty and decreased muscle mass potentially contribute to increased morbidity risk. Objective: This study aimed to investigate the associations between lean muscle loss and gray matter volume (GMV) in PD patients. Methods: Thirty patients with PD and fifteen healthy controls underwent brain and bilateral thigh MRIs. The IDEAL sequence was employed, measuring the regions of interest (ROI) of fat percentage at the 50% point of femur length. Voxel-base morphometry (VBM) was used to assess regional gray matter volume differences between groups. Further correlation analysis was performed to evaluate the changes between gray matter volume and fatty percentage of the bilateral thigh after adjusting for age and gender. Multiple linear regression analysis was applied to evaluate the risk factor of core muscle loss in PD patients. Results: Compared with controls, patients with PD had significantly higher thigh fat percentage and smaller gray matter volume of several brain locations of the default mode network (DMN), specifically the left superior temporal gyrus, right uncus, and left inferior temporal gyrus, revealing association with higher thigh fat percentage. Further multiple linear regression analysis indicated that higher thigh fat percentage is associated with gender (female), increased disease duration, and smaller gray matter volume of the left superior temporal gyrus and right uncus in PD patients. Conclusions: Patients with PD experience core muscle loss in the thigh, associated with default mode network (DMN) degeneration, longer disease duration, and female gender. Identification of risk factors associated with lean muscle mass loss may assist in early prevention of comorbidities such as sarcopenia.