Background: Children with physical health long-term conditions (LTCs) have increased risk of mental health difficulties relative to healthy peers. However, availability of psychological support integrated into pediatric physical health settings is limited, and there are long waiting times for access to child mental health services. Arts-based therapies involve using creative media to develop a therapeutic relationship, and offer a potential alternative to talking-based therapies. The aim of this systematic review is to establish the effectiveness of arts-based therapies for improving the mental health of children with physical health LTCs. Methods: The review protocol was published on PROSPERO. Four electronic databases were searched (Medline, Embase, Cinahl, and PsycINFO), plus hand searches of two key journals and relevant reviews, and forward/back citations searches of selected articles were conducted. The Effective Public Health Practice Project (EPHPP) Quality Assessment Tool was used to assess bias in selected articles. Second reviewers completed 10% of article screening and 20% of bias assessments. The findings were synthesized narratively. Results: Sixteen studies met inclusion criteria and demonstrated some improvements on indicators of mental health and well-being including quality of life, coping behaviors, anxiety, self-concept, and mood. However, replication across interventions and outcomes was absent. Overall, the quality of evidence of effectiveness in the studies reviewed was moderate/weak. This was due to bias in study design; other limitations included a lack of detail on intervention components, e.g., use of a manual, and single recruitment sites. Conclusions: The heterogeneity of existing research evaluating arts-based therapies for children with physical health LTCs limits conclusions about effectiveness. Suggestions are made to inform the design of future research studies to help build a robust evidence base.