Emergence of malaria parasites resistant to artemisinin necessitates the need for development of new antimalarial therapies. Ciprofloxacin (CFX) a second generation quinolone antibiotic possesses some antimalarial activities. We investigated the in vivo antimalarial activities of CFX in combination with amodiaquine in mice infected with chloroquine-resistant Plasmodium berghei ANKA. Animals were treated orally with 80 or 160 mg kg−1 body weight of CFX alone given twice daily or in combination with amodiaquine (AQ) 10 mg kg−1 body weight. Parasitological activity and survival of the animals were assessed over 21 days. Peak parasitaemia in the untreated control group was 72·51%. Treatment with AQ alone resulted in clearance of parasitaemia by day 4 while treatment with CFX 80 and 160 mg kg−1 alone suppressed parasitaemia by 13·94–54·64% and 35·6–92·7%, respectively. However, the combination of CFX with AQ significantly enhanced response of infection in the animals to treatment (P < 0·05) resulting in complete resolution of parasitaemia throughout follow up period with CFX 160 mg kg−1, delayed recrudescence time with CFX 80 mg kg−1 and significant increase in survival rate of the animals. The results demonstrate beneficial interaction between AQ and CFX which may provide a clinically relevant antimalarial/antibiotic therapeutic option in the management of malaria.