Increasing cultural and linguistic diversities of populations have created a challenge for medical educators to provide authentic learning experiences fostering cross-cultural understanding and interprofessional attitudes of students. Simulations with actors portraying patients (commonly referred to as simulated patients) are effective learning modalities to teach students to provide culturally competent care and influence the quality of patient-centered care. The aim of this systematic review was to identify and synthesize available evidence on the use of simulations with simulated patients as a learning intervention to teach cultural competence to the students of healthcare professions. The PubMed, Medline Complete, and CINAHL databases were searched for articles, which resulted in 27 papers being included in the review. Results revealed that engaging students in cross-cultural interactions with patients increases their level of cultural competence, confidence, and learning satisfaction, and therefore, simulations with simulated patients can serve as a powerful reinforcement of cross-cultural education.