The search for newer antimalarial drug combinations is on the front burner due to rising Plasmodium resistance to some currently used antimalarial drugs. This study examined the antiplasmodial activity of sulfadoxine/pyrimethamine/doxycycline (S/P/D) on mice infected with Plasmodium berghei (P. berghei). Swiss albino mice (25-30 g) inoculated with P. bergei (1x107) were treated with D (2.2 mg/kg), S/P (21.4/10.7 mg/kg), and S/P/D for 4 days. The positive and negative controls were treated with normal saline (0.2 ml) and chloroquine (CQ) (10 mg/kg) for 4 days, respectively. After treatment, blood samples were collected and assessed for parasitemia levels and biochemical parameters. The mice were observed for mean survival time (MST). D, S/P, S/P/D and CQ significantly decreased parasitemia in the curative, prophylactic and suppressive tests at p<0.05; p<0.01, p<0.001 and p<0.001, respectively when compared to negative control. In the curative study, 55.9%, 65.1%, and 81.7% parasitemia inhibitions were produced by D, S/P and S/P/D, respectively whereas CQ produced 75.6 % parasitemia inhibition. D, S/P and S/P/D significantly prolonged MST at p<0.05, p<0.01 and p<0.001 respectively when compared to negative control. Altered serum biochemical markers in P. berghei infected mice were marked by significantly (p<0.001) decreased packed cell volume, red blood cells, hemoglobin, high density lipoprotein cholesterol levels with significantly (p<0.001) increased cholesterol, white blood cells, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels when compared to control. However, D, S/P and S/P/D significantly restored the aforementioned markers at p<0.05, p<0.01 and p<0.001, respectively when compared to negative control. S/P/D may be used as an antimalarial drug.