Introduction Children with thalassemia often require repeated invasive treatments and frequent hospitalizations, resulting in pain, anxiety, and altered vital signs. Implementing non-invasive, non-pharmacological, and inexpensive complementary practices can benefit both the child and their family. Aim This study aimed to evaluate the impact of foot reflexology versus simple massage on vital signs, anxiety, and pain induced by blood transfusions in children with thalassemia. Materials and methods  An experimental study was conducted on 60 children with thalassemia; children aged 2-13 years were selected by systematic random sampling. The participants were separated into two groups: 30 children received foot reflexology and 30 children received a simple massage. Data were collected using a self-structured demographic profile, vital signs record sheet, standard Observational Scale of Behavioral Distress-Revised (OSBD-R) scale, and visual analog scale (VAS). Paired and unpaired t-tests were used to evaluate the effects of the interventions. The chi-square test was utilized to evaluate the relationship between demographic and dependent variables. Result Foot reflexology showed a significant difference (P < 0.05) in systolic and diastolic blood pressure and a highly significant difference (P < 0.0001) in anxiety and pain. The simple massage group showed a significant effect on temperature, anxiety, and pain. Both groups demonstrated a significant impact (P < 0.05) on systolic blood pressure and pain after the intervention. Conclusion  Most children were diagnosed with thalassemia during infancy, had a history of both parent's thalassemia minor, and were Rh+ve. Foot reflexology was more effective in reducing anxiety and pain than simple massage. Additionally, foot reflexology had a significant effect on systolic and diastolic blood pressure, while simple massage significantly affected temperature in children with thalassemia.