When physicians and nurses are looking at the same patient, they may not see the same picture. If assuming that the clinical reasoning of both professions is alike and ignoring possible differences, aspects essential for care can be overlooked. Understanding the multifaceted concept of clinical reasoning of both professions may provide insight into the nature and purpose of their practices and benefit patient care, education and research. We aimed to identify, compare and contrast the documented features of clinical reasoning of physicians and nurses through the lens of layered analysis and to conduct a simultaneous concept analysis. The protocol of this systematic integrative review was published doi: 10.1136/bmjopen-2021-049862. A comprehensive search was performed in four databases (PubMed, CINAHL, Psychinfo, and Web of Science) from 30th March 2020 to 27th May 2020. A total of 69 Empirical and theoretical journal articles about clinical reasoning of practitioners were included: 27 nursing, 37 medical, and five combining both perspectives. Two reviewers screened the identified papers for eligibility and assessed the quality of the methodologically diverse articles. We used an onion model, based on three layers: Philosophy, Principles, and Techniques to extract and organize the data. Commonalities and differences were identified on professional paradigms, theories, intentions, content, antecedents, attributes, outcomes, and contextual factors. The detected philosophical differences were located on a care-cure and subjective-objective continuum. We observed four principle contrasts: a broad or narrow focus, consideration of the patient as such or of the patient and his relatives, hypotheses to explain or to understand, and argumentation based on causality or association. In the technical layer a difference in the professional concepts of diagnosis and the degree of patient involvement in the reasoning process were perceived. Clinical reasoning can be analysed by breaking it down into layers, and the onion model resulted in detailed features. Subsequently insight was obtained in the differences between nursing and medical reasoning. The origin of these differences is in the philosophical layer (professional paradigms, intentions). This review can be used as a first step toward gaining a better understanding and collaboration in patient care, education and research across the nursing and medical professions.