Background <p>This study aims to examine whether egocentric-based mental rotation is affected in individuals with Multiple Sclerosis (MS) and to analyze its relationship with disability, functional system scores (FSS), and cognitive parameters.</p> Methods <p>The study involved 57 right-dominant individuals with MS and 40 right dominant healthy subjects. Disability was assessed using the Neurostatus-Expanded Disability Status Scale (Neurostatus-EDSS). Participants’ performance on mental rotation tasks was evaluated with the Recognise Hand App™, Recognise Foot App™, measuring reaction times (seconds) and accuracy (%) for hand and foot stimuli. Cognitive functioning was assessed using the Brief International Cognitive Assessment for MS (BICAMS).</p> Results <p>MS patients exhibited lower performance in right hand mental rotation reaction time (<i>p</i> = 0.042), right hand accuracy percentage (<i>p</i> &lt; 0.001), right foot accuracy percentage (<i>p</i> = 0.035). Positive correlations were found between disease duration, EDSS total score, cerebellar FSS, bladder-bowel FSS, and ambulation scores with reaction times, while negative correlations were observed with accuracy percentages (<i>p</i> &lt; 0.05). Additionally, a positive correlation was identified between accuracy percentages and BICAMS (<i>p</i> &lt; 0.05).</p> Conclusions <p>The study revealed substantial impairments in right-hand and right-foot performance in right dominant individuals with MS. Mental rotation abilities were found to be related to disease duration, higher EDSS and FSS scores, as well as cognitive functioning. Identifying the cognitive domains and functional systems associated with egocentric mental rotation will contribute to better understanding this underexplored area and developing potential treatment strategies to enhance functionality.</p>