Background: Spiritual health has been linked to the mental health of adolescents. Yet, the impact of the coronavirus pandemic on the spiritual health of adolescents with chronic diseases, as opposed to the mental health of their healthy counterparts in Iran, has not been explored. Objectives: The aim of this study was to examine the association between spiritual health and COVID-19-induced anxiety among adolescents, both with and without chronic diseases. Methods: This descriptive cross-sectional study involved 85 adolescents with chronic diseases (selected through convenience sampling) and 80 adolescents without chronic diseases (selected through cluster random sampling) in Tehran, Iran. The Spiritual Well-Being Scale (SWBS) and the Corona Disease Anxiety Scale (CDAS) were utilized for data collection. Results: The findings indicated that anxiety levels related to COVID-19 were significantly higher among adolescents with chronic diseases compared to their healthy peers (P = 0.001). Additionally, spiritual well-being was significantly lower in adolescents with chronic diseases than in healthy adolescents (P = 0.001). Conclusions: The COVID-19 pandemic appears to be linked to psychological and spiritual vulnerabilities in adolescents with chronic diseases, suggesting a need for psychological support and special consideration for these individuals.