One of the hallmarks of malaria infection is oxidative stress. This study was aimed at investigating the potential effects of coadministering a therapeutic dose of artesunate–amodiaquine (AS/AQ) with Vitamin C (Vit C) orally on some biochemical parameters and antioxidant enzymes gene expression in bone marrow cells of Plasmodium berghei-infected mice. Thirty male Swiss albino mice were divided into five groups of six mice each as follows: Basal control (not infected with P. berghei), Untreated (P. berghei-infected without treatment), Vit C, AS/AQ and AS/AQ + Vit C combination treated mice. Treatment was done twice daily for three consecutive days. Complete parasite clearance was observed on the second day of treatment in AS/AQ and AS/AQ + Vit C combination treated P. berghei-infected mice. Serum albumin and bilirubin levels were higher in the AS/AQ + Vit C combination treated P. berghei-infected mice compared with those treated with AS/AQ only. Artesunate–amodiaquine + Vit C combination increased superoxide dismutase activity and reduced hydrogen peroxide and malondialdehyde levels in P. berghei-infected mice when compared with the mice treated with only AS/AQ. Furthermore, AS/AQ + Vit C combination significantly up-regulated catalase and glutathione peroxidase-1 (GPx-1) mRNA expression compared with the mice treated with only AS/AQ. This is the first report linking AS/AQ to antioxidant enzyme gene expression in bone marrow cells. Our findings showed that AS/AQ and Vit C coadministration may be beneficial as it ameliorated oxidative stress and up-regulated antioxidant enzyme gene expression in P. berghei-infected mice.