AIM: Sickle cell disease (SCD) is a major public health concern. Self-efficacy is a person's particular set of beliefs in their ability to accomplish daily life activities with symptom management. The aim of the present study was to explore the level of self-efficacy among adolescents with SCD. METHODS: A descriptive cross-sectional study was conducted to assess the self-efficacy of adolescents with sickle cell disease using a purposive sampling of 300 adolescents diagnosed with SCD in a tertiary care center in east-central India. A sickle cell self-efficacy scale was used to collect data between November 2023 and April 2024. Data was analyzed using descriptive statistics and linear regression. RESULTS: The mean age at which adolescents were diagnosed with SCD was 3.31 ± 0.14 years, and 69.7% (209) of adolescents were identified between the ages of one and five years. Additionally, 73% (219) of adolescents had moderate self-efficacy. The current study found that most adolescents had a moderate level of self-efficacy, and regression analysis showed that the strong predictors for higher self-efficacy levels were higher education, economic status, place of residence, and age group. CONCLUSIONS: The adolescents had a moderate level of self-efficacy. Future interventions are recommended to help improve self-efficacy in adolescents with SCD.