Background Continuing professional development (CPD) is essential for physicians to maintain and enhance their knowledge, competence, skills, and performance. Web-based CPD plays an essential role. However, validated theory–informed measures of their impact are lacking. The CPD-REACTION questionnaire is a validated theory–informed tool that evaluates the impact of CPD activities on clinicians’ behavioral intentions. Objective We aimed to review the use of the CPD-REACTION questionnaire, which measures the impact of CPD activities on health professionals’ intentions to change clinical behavior. We examined CPD activity characteristics, ranges of intention, mean scores, score distributions, and psychometric properties. Methods We conducted a systematic review informed by the Cochrane review methodology. We searched 8 databases from January 1, 2014, to April 20, 2021. Gray literature was identified using Google Scholar and Research Gate. Eligibility criteria included all health care professionals, any study design, and participants’ completion of the CPD-REACTION questionnaire either before, after, or before and after a CPD activity. Study selection, data extraction, and study quality evaluation were independently performed by 2 reviewers. We extracted data on characteristics of studies, the CPD activity (eg, targeted clinical behavior and format), and CPD-REACTION use. We used the Mixed Methods Appraisal Tool to evaluate the methodological quality of the studies. Data extracted were analyzed using descriptive statistics and the Student t test (2-tailed) for bivariate analysis. The results are presented as a narrative synthesis reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results Overall, 65 citations were eligible and referred to 52 primary studies. The number of primary studies reporting the use of CPD-REACTION has increased continuously since 2014 from 1 to 16 publications per year (2021). It is available in English, French, Spanish, and Dutch. Most of the studies were conducted in Canada (30/52, 58%). Furthermore, 40 different clinical behaviors were identified. The most common CPD format was e-learning (34/52, 65%). The original version of the CPD-REACTION questionnaire was used in 31 of 52 studies, and an adapted version in 18 of 52 studies. In addition, 31% (16/52) of the studies measured both the pre- and postintervention scores. In 22 studies, CPD providers were university-based. Most studies targeted interprofessional groups of health professionals (31/52, 60%). Conclusions The use of CPD-REACTION has increased rapidly and across a wide range of clinical behaviors and formats, including a web-based format. Further research should investigate the most effective way to adapt the CPD-REACTION questionnaire to a variety of clinical behaviors and contexts. Trial Registration PROSPERO CRD42018116492; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=116492