Objective: To assess the occurrence and pattern of Toll-like receptor 4 (TLR4) co-segregated genotypes among children with Plasmodium falciparum malaria in Nigeria. Methods: In this case-control study, a total of 79 Plasmodium falciparum infected children aged 2–7 years and 105 age-matched uninfected controls of Yoruba descents in Lagos were studied. The extracted DNA samples were used for TLR4 genotyping at codons 299 (Asp > Gly) and 399 (Thr > Ile) by PCR-restriction fragment length polymorphism. Malaria infection was diagnosed by blood smear microscopy and infected children were stratified into asymptomatic, uncomplicated and severe malaria sub-groups. Malnutrition was determined by measuring the mid upper arm circumference and anemia was defined as hemoglobin < 11 g/dL. Results: The proportions of children with acute malnutrition and severe anemia were 12.0% and 3.2%, respectively. Parasitemia and malnutrition were not correlated and four distinct patterns of TLR4 genotypes were found in the study population: Asp299Asp/Thr399Thr (90.2%), Asp299Gly/Thr399Thr (4.3%), Gly299Gly/Thr399Thr (3.8%) and Asp299Gly/Thr399Ile (1.6%). These genotypes did not differ significantly (P > 0.05) in frequency between infected and non-infected children. However, low and high occurrences of the TLR4 Asp299Asp/Thr399Thr and Asp299Gly/Thr399Thr genotypes were observed in the severe malaria subgroup. Conclusions: This study reveals a protective role for TLR4 Asp299Gly/Thr399Ile and Asp299Asp/Thr399Thr genotypes against severe malaria in Nigerian children.