Background: Numerous studies have evaluated the effect that mindfulness-based interventions (MBIs) have on multiple health outcomes. For its part, stress is a natural response to environmental disturbances and within the associated metabolic responses, alterations in cortisol levels and their measurement in different tissues are a way to determine the stress state of an individual. Therefore, it has been proposed that MBIs can modify cortisol levels. Methods and results: The objective of this systematic review was to analyze and summarize the different studies that have evaluated the effect of MBIs on cortisol levels. The following databases were consulted: MEDLINE, AMED, CINAHL, Web of Science, Science Direct, PsycINFO, SocINDEX, PubMed, the Cochrane Library and Scopus. The search terms “mindfulness”, “mindfulness-based interventions” and “cortisol” were used (and the search was limited to studies from January 1990 to May 2024). In order to reduce selection bias, each article was scrutinized using the JBI Critical Appraisal Checklist independently by two authors. We included those studies with specified intervention groups with at least one control group and excluded duplicate studies or those in which the intervention or control group was not adequately specified. Significant changes in cortisol following MBIs were found in 25 studies, while 10 found no changes. The small sample size, lack of randomization, blinding, and probable confounding and interaction variables stand out in these studies. Conclusion: MBIs have biological plausibility as a means of explaining a positive effect on cortisol levels; however, the weakness of the studies and the absence of robust designs makes it difficult to establish a causal association between both variables. Registration number: INPLASY2024110017.