Aims: The aim of this study was to assess the impact of hemoglobin polymorphisms and G6PD deficiency on the course of uncomplicated malaria infection in children aged from 2 to 10 years in Burkina Faso. Study Design: The study was conducted as a longitudinal study in Banfora health district. A total of 150 children aged from 2 to 10 years was enrolled and followed up between May 2015 and February 2016. Blood samples were collected at four different time points: before infection (Visit 1), during asymptomatic parasitemia (Visit 2), during symptomatic parasitemia (Visit 3) and three weeks after treatment (Visit 4). Clinical examination, hematology parameters and malaria diagnosis using microscopy were performed. Hemoglobin and G6PD typing were done using PCR-RFLP. Hemoglobin AA genotypes were defined as normal hemoglobin while Hemoglobin AC, AS and SS were defined as abnormal hemoglobin (hb non-AA). Results: The prevalence of hemoglobin (hb) genotypes was 81.21% for AA while hb non-AA genotypes were estimated at 18.79% (12.08% for hbAC, 6.04% for hbAS and 0.67% for HbSC). The prevalence of G6PD genotypes was 89.26% and 10.74% for normal G6PDn and G6PD deficiency respectively. The prevalence of asymptomatic carriers of P. falciparum was not affected neither by the genotypes of Hemoglobin, nor by the G6PD deficiency. Conversely, the risks of developing uncomplicated malaria in G6PD deficiency (G202A) group, was significantly lower (p = 0.04). The results showed a significant difference (p˂0.0001) in the means of P. falciparum parasite densities between asymptomatic and symptomatic phase in Hemoglobin AA genotypes carriers while the means of parasite density was comparable in non-Hemoglobin AA carriers. Conclusion: Our study showed that G6PD deficiency protects against clinical malaria while P. falciparum parasite density increasing was correlated with carrying hemoglobin genotypes AA.