Background: Migrants and refugees are high-risk populations with often limited health literacy (HL). It is crucial to improve their HL early after arrival. One promising approach is to combine language and HL learning in second-language courses. Objectives: This study reviewed empirical evidence on the promotion of migrants’ HL in second-language courses and developed a theory of change to inform innovative projects. Methodology: We conducted a systematic realist review of HL in second language courses in seven scientific databases and a grey literature search. After screening titles, abstracts, and full texts, we identified 21 eligible publications from 13 programs. We systematically analyzed program context and characteristics, evaluation design, and outcomes and developed a theory of change based on the findings. Results: Programs promoting HL in second language courses are diverse in terms of contextual factors, formats, study designs, measures of HL, language improvements, effectiveness, relevant outcomes, and enabling factors. All studies reported improved HL after the program, but to varying degrees. The findings regarding second language improvement are mixed. Seven core components of HL as a social practice emerged. Numerous factors influencing course implementation, outcomes, and sustainability were described in detail. We conceptualized a theory of change for the HL promotion in second language courses. Conclusion: This realist review presents ample empirical evidence that second language courses can promote HL in various ways. However, these courses are complex, heterogeneous, and dependent on multiple factors. Despite these limitations, second language courses show promise as innovative and effective approaches that reach many migrants. Therefore, health promoters, medical professionals, adult educators, and policymakers should collaborate nationally and internationally to leverage this unique opportunity. The theory of change can serve as a blueprint for discussing existing programs thoroughly and developing promising, effective, and sustainable programs.