Malaria remains a critical global health challenge that requires improved prophylactic strategies. We evaluated the dose-dependent prophylactic antiplasmodial activity of curcumin (CUR) against Plasmodium berghei in mice and compared it with that of dihydroartemisinin (DHA) and distilled water, and assessed haematological effects, bodyweight changes, and pharmacokinetic interactions between CUR and DHA in rats. Swiss albino mice received CUR at 25, 50, or 100 mg/kg, DHA at 2.2 mg/kg, or distilled water orally for 3 days before infection. Parasitaemia was quantified from Giemsa-stained smears; haematological parameters (red blood cells [RBC], haemoglobin [HGB], haematocrit [HCT], mean corpuscular volume [MCV]) and body weight were measured. In rats, the effect of CUR (100 mg/kg) on DHA serum concentrations was characterized from concentration–time data. CUR showed dose-dependent parasite clearance (55%, 80%, and 92% at 25, 50, and 100 mg/kg, respectively), comparable to DHA (95%; p < 0.05). CUR at 50 mg/kg significantly increased RBC, HGB, HCT, and MCV compared with DHA (p < 0.05), and all CUR doses mitigated infection-related weight loss similar to DHA. Co-administration of CUR did not reduce DHA exposure (area under the curve and Cmax unchanged), although half-life increased and elimination rate decreased, indicating prolonged distribution without altered clearance. Curcumin demonstrated dose-dependent prophylactic antiplasmodial activity, hematoprotective effects, and no detrimental pharmacokinetic interaction with DHA, supporting its potential as an adjunctive prophylactic agent in malaria management.