Abstract Background Health policy and systems research (HPSR) is an inherently cross-disciplinary field of investigation. However, conflicting conceptualisations about inter-, multi- and transdisciplinary research have contributed to confusion about the characteristics of cross-disciplinary approaches in HPSR. This review was conducted to (1) define the characteristic features of context–mechanism–outcome (CMO) configurations in cross-disciplinary HPSR, (2) develop criteria for evaluating cross-disciplinarity and (3) synthesise emerging challenges of the approach. Method The paper is a critical realist synthesis conducted in three phases, as follows: (1) scoping the literature, (2) searching for and screening the evidence, and (3) extracting and synthesising the evidence. Five databases, namely the International Bibliography of the Social Sciences and Web of Science, PubMed central, Embase and CINHAL, and reference lists of studies that qualified for inclusion in the review were searched. The search covered peer-reviewed original research, reviews, commentary papers, and institutional or government reports published in English between January 1998 and January 2020. Results A total of 7792 titles were identified in the online search and 137 publications, comprising pilot studies as well as anecdotal and empirical literature were selected for the final review. The review draws attention to the fact that cross-disciplinary HPSR is not defined by individual characteristics but by the combination of a particular type of research question and setting (context), a specific way of researchers working together (mechanism), and research output (outcome) that is superior to what could be achieved under a monodisciplinary approach. This CMO framework also informs the criteria for assessing whether a given HPSR is truly cross-disciplinary. The challenges of cross-disciplinary HPSR and their accompanying coping mechanisms were also found to be context driven, originating mainly from conceptual disagreements, institutional restrictions, communication and information management challenges, coordination problems, and resource limitations. Conclusion These findings have important implications. First, the CMO framework of cross-disciplinary HPSR can provide guidance for researchers engaging in new projects and for policy-makers using their findings. Second, the proposed criteria for evaluating theory and practice of cross-disciplinary HPSR may inform the systematic development of new research projects and the structured assessment of existing ones. Third, a better understanding of the challenges of cross-disciplinary HPSR and potential response mechanisms may help researchers to avoid these problems in the future.