This study’s objective was to assess the relationship between serum cytokine levels and the occurrence of pulp necrosis (PN) and apical periodontitis (AP) in adolescents with Sickle Cell Disease (SCD). A total of 52 adolescents, including 29 individuals diagnosed with SCD, participated in the study. Serum cytokine levels including IL-1, IL-2, IL-4, IL-6, IL-1β, IL-8, IL-10, IL-17, and TNF-α were analyzed. Radiological and intraoral dental examinations were conducted on the same day. Electric pulp testing and cold tests were conducted on all intact crowned teeth to assess the presence of PN. Periapical index scores were derived from panoramic and periapical radiographs to identify teeth exhibiting AP. Statistical analyses were carried out using Student’s t-test, Chi-square test, Spearman correlation test, and the Mann–Whitney U test. In the SCD group, the levels of IL-2, IL-4, IL-6, IL-8, IL-17, and TNF-α were significantly higher compared to the control group (p < 0.001, < 0.001, < 0.001, < 0.001, < 0.001, and = 0.003, respectively). No statistically significant association was observed between the groups and PN status (p = 0.06). Among individuals with SCD, IL-8 and TNF-α levels were significantly higher in those with apical periodontitis (AP+) compared to those without apical periodontitis (AP−) (p < 0.05). Statistically significant differences in IL-8 and TNF-α levels were observed between the AP (+) SCD group and the AP (+) control group (p = 0.004 for both). Additionally, significant differences in IL-2, IL-4, IL-6, IL-8, and IL-17 levels were found between the AP (-) SCD group and the AP (-) control group (p = 0.001 for all comparisons). IL-8 and TNF-α may be associated with the presence of apical periodontitis in SCD. In adolescents with SCD, disease-related serum cytokine levels may be associated with apical lesions. Additionally, these apical lesions may not be the primary cause of PN. As with other oral and dental conditions, early detection of apical lesions is crucial, and appropriate treatment plans should be developed. Collaborative efforts between dentists and hematologists are essential in managing these cases effectively.