The Multiple Sclerosis Work Difficulties Questionnaire-23 (MSWDQ-23) is a self-report instrument developed to assess barriers faced by People with Multiple Sclerosis (PwMS) in the workplace. The aim of this study was to explore the psychometric properties of the Greek version of the MSWDQ-23. The study sample consisted of 196 PwMS, all currently working in part- or full-time jobs. Participants underwent clinical examination and cognitive screening with the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) and completed self-report measures of fatigue, psychological functioning, and quality of life, along with the MSWDQ-23 questionnaire. Confirmatory Factor Analysis (CFA) was performed, and goodness-of-fit measures were used to evaluate construct validity. Convergent validity was checked by correlating MSWDQ-23 scores with study measures. Cronbach’s alpha value was produced to assess internal consistency. CFA yielded a model with a fair fit confirming the three-factor structure of the instrument. Higher work difficulties were associated with higher Expanded Disability Status Scale (EDSS) scores, poorer cognitive function, more fatigue, stress, anxiety, and depression, and poorer health status, supporting the convergent validity of MSWDQ-23. Internal consistency (Cronbach’s alpha = 0.94) and test–retest reliability (ICC = 0.996, 95%, CI = 0.990–0.998) were excellent. The Greek MSWDQ-23 can be considered a valid patient-reported outcome measure and can be used in interventions aiming to improve the vocational status of PwMS.