The characteristics of the school environment can influence students’ participation. Therefore, exploring the existing barriers to school participation and academic success of students with chronic conditions (CCs) is essential since they are a population at an increased risk for impairments and difficulties in these areas. This specific study aimed to explore the personal and school-environment variables associated with the school participation of students with CCs. Additionally, it aimed to analyze the differences between (1) male and female adolescents concerning the impact of CCs on school participation and the personal and school-environment variables; and (2) adolescents with and without school participation affected by the existing CCs regarding personal and school-environment variables. This work included 1442 adolescents with CCs, 56.3% female (n = 769), with a mean age of 15.17 years (SD = 2.33), participating in the Health Behavior in School-Aged Children (HBSC) 2022 study. The results showed that girls and students with school participation affected by CCs are at greater risk regarding the personal and school-environment variables under study. In the multivariable logistic regression analysis of the association between these variables and the school participation of students with CCs, a greater weight of personal variables was observed, followed by those of the school environment related to interpersonal relationships and, finally, the physical environment and safety-at-school variables. The study highlights the relevance of considering the existing barriers to school participation and academic success of students with CCs. The results also underline the importance of aligning the intervention of health and education professionals and policymakers. All of these professionals must make a joint effort to overcome existing barriers in the school context and move towards an increasingly balanced environment that promotes and protects the equal participation of all students.