Background Sickle cell disease (SCD) is a prevalent inherited hemoglobinopathy characterized by chronic hemolytic anemia, vaso-occlusive crises (VOC), and multi-organ complications. Blood transfusion plays a critical role in the management of both acute and chronic complications associated with SCD, including stroke, acute chest syndrome (ACS), and splenic sequestration. However, the variability in transfusion practices and associated risks, such as alloimmunization and iron overload, necessitates further investigation into optimizing transfusion strategies in pediatric SCD patients. Objectives This study aimed to identify the most common indications for blood transfusion and exchange transfusion in pediatric patients with SCD at King Salman Armed Forces Hospital (KSAFH) in Tabuk, Saudi Arabia, from June 2020 to June 2024. By analyzing transfusion patterns and their outcomes, we sought to provide insights into improving transfusion management in this population. Methods An observational cross-sectional study was conducted on 99 pediatric SCD patients aged 1 to 14 years who received transfusions at KSAFH. Data were collected retrospectively from electronic medical records, including patient demographics, transfusion indications, hemoglobin levels, and adverse reactions. Descriptive statistical methods were used to assess the prevalence of various transfusion indications, and chi-square and analysis of variance (ANOVA) tests were applied to evaluate associations between clinical variables and transfusion outcomes. Results The study found that 68 patients (68.7%) required multiple transfusions, with exchange transfusions being used in 32 patients (31.3%), primarily for severe complications. ACS was the leading indication for transfusion, occurring in 32 patients (32.3%), followed by hemolytic crisis in 18 patients (18.2%), stroke prevention in 11 patients (11.1%), and splenic sequestration in eight patients (8.1%). Preoperative transfusions were administered to eight patients (8.1%), while seven patients (7.1%) required transfusions for aplastic crisis. More than 75% of ACS cases were managed with simple transfusions, and all showed significant improvement. Hydroxyurea non-compliance was notably high, with 64 patients (64.6%) not adhering to the regimen. Adverse transfusion reactions were rare, occurring in only four patients (4%), with fever being the most common reaction. Conclusions Blood transfusion remains an essential component of managing pediatric SCD, particularly for ACS, stroke prevention, and other severe complications. Simple transfusions were observed to be effective in many ACS cases, suggesting a role for less invasive interventions in specific clinical contexts. However, variability in transfusion practices and the high rate of hydroxyurea non-compliance highlight the need for standardized transfusion guidelines and enhanced patient education.