Clinical reasoning training in the pre-clinical phase has recently been considered important; however, when it comes to specific instructional methods for pre-clinical students, much is unknown. Thus, the aim of this review is to explore learning and teaching methods for pre-clinical students’ clinical reasoning development based on illness script formation, their results, and strategies. A systematic review was conducted in accordance with the guidelines of the Association for Medical Education in Europe. The literature search was performed using the Cochrane Library, PubMed, EMBASE, Web of Science, and ERIC databases based on keywords, including “illness script*” AND (“medical student*” OR pre-clinical OR undergraduate). Then, 10 studies among the 91 studies were included in the final analysis. The quality of the selected studies was also appraised using the Medical Education Research Study Quality Instrument. Diverse teaching and learning methods were used to support the integration of biomedical and clinical knowledge working with patient cases, and their effects were assessed through diverse methods, including illness script richness and maturity, to learner responses. The effects of these interventions were effective in terms of the clinical reasoning development of pre-clinical students. Learning and teaching strategies were synthesized and described. This review found that explicit attempts to promote illness script formation with a structured program rather than informal training lead to positive results, and such formal clinical reasoning programs can provide smooth transition from pre-clinical to clinical experience.