Objectives: Symptomatic treatment is an essential component in the overall treatment of multiple sclerosis (MS). However, knowledge in this regard is confusing and scattered. Physicians also have challenges in choosing symptomatic treatment based on the patient’s condition. To share, update, and reuse this knowledge, the aim of this study was to provide an ontology for MS symptomatic treatment. Methods: The Symptomatic Treatment of Multiple Sclerosis Ontology (STMSO) was developed according to Ontology Development 101 and a guideline for developing good ontologies in the biomedical domain. We obtained knowledge and rules through a systematic review and entered this knowledge in the form of classes and subclasses in the ontology. We then mapped the ontology using the Basic Formal Ontology (BFO) and Ontology for General Medical Sciences (OGMS) as reference ontologies. The ontology was built using Protégé Editor in the Web Ontology Language format. Finally, an evaluation was done by experts using criterion-based approaches in terms of accuracy, clarity, consistency, and completeness. Results: The knowledge extraction phase identified 110 articles related to the ontology in the form of 626 classes, 40 object properties, and 139 rules. Five general classes included “patient,” “symptoms,” “pharmacological treatment,” “treatment plan,” and “measurement index.” The evaluation in terms of standards for biomedical ontology showed that STMSO was accurate, clear, consistent, and complete. Conclusions STMSO is the first comprehensive semantic representation of the symptomatic treatment of MS and provides a major step toward the development of intelligent clinical decision support systems for symptomatic MS treatment.