Antioxidant enzymes can contribute to disease susceptibility or determine response to therapy in individuals with malaria. Genetic variations due to polymorphisms in host genes encoding antioxidant enzymes such as glutathione S-transferases-theta, mu, pi (GSTT, GSTM, GSTP), superoxide dismutases (SOD) and catalase (CAT), may therefore, influence inter-individual response to malaria pathology and propensity of infection caused by Plasmodium vivax (Pv) and Plasmodium falciparum (Pf). Therefore, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and DNA sequencing, we investigated the association of deletions of GSTT1 and GSTM1, single nucleotide polymorphisms (SNPs) of GSTP1 (rs1695), SOD1 (rs2234694), SOD2 (rs4880, rs1141718), SOD3 (rs2536512) and CAT (rs1001179) in individuals infected with Pf (n = 100) and Pv (n = 100) against healthy controls (n = 150). Our data suggest a significant role for GSTM1 deletions in complicated Pv (p = 0.0007) malaria with ODDs ratio 3.8 [with 95 % confidence interval (CI) 1.9-7.4]. The results also indicated that polymorphisms present in GSTP1, SOD1 and CAT genes may be associated with malaria susceptibility (p < 0.05), whereas SOD3 polymorphism may play a role in malarial resistance (p < 0.05). In addition, we observed significant SNP-SNP interactions with synergistic genetic effects in SOD2, SOD3 and CAT genes for Pv and in SOD2 and SOD3 genes for Pf. In conclusion, our results provide convincing evidence for a relationship between polymorphisms in host antioxidant enzymes and susceptibility to malaria infection.