Background:  Sickle cell disease has become a common inherited hemoglobin disorder. Various reports have shown that a high mortality rate of children under five years of age was reported in the year 2022 in Tanzania. This research aimed to determine the prevalence of sickle cell disease (SCD) amongst children under five years of age and their family history at Heri Mission Hospital in Buhigwe District, Kigoma.  Methods:  A convenient cross-sectional study was carried out to enroll 204 children under the age of five years at Heri Mission Hospital. The collected data were subjected to analysis of variances using the statistical package for Social Sciences (SPSS) version 28.0.1.0 software (SPSS Inc., USA). The Chi-square test was utilized in comparing proportions and frequency of occurrence of Haemoglobin (Hb) in the variables at P < 0.05 as the significance of variance.  Results:  The prevalence of SCD among children under five years was 28.3% (103/364). Among the positively tested with SCD, the majority were female at 71.7% (65/91), whereas males were 28.3% (26/91). Family records of the children with SCD showed that the proportional of SCD was significantly higher among family members with SCD 73.1% (38/52) than none SCD (14/52) 26.9% (X2 = 7.513, P < 0.05).  Conclusion:  The findings in this research showed a high rate of SCD amongst children under five years, and the family history of the victims showed it’s inheritable.  Recommendation:  Health awareness and proper mitigation strategies need to be addressed on how to curb the SCD in Buhigwe District and Tanzania as a country.