Antimalarial drug-resistance has become a critical global issue, thereby making the search for novel and effective antimalarials imperative. This study aimed at designing, synthesising, and evaluating the antiplasmodial properties of quercetin and some of its derivatives. Forty quercetin derivatives were designed with ChemDraw and docked on six antimalarial targets using AutoDock Vina. Two ligands with the best binding affinity were synthesised using standard methods and characterised using UV-Vis and FT-IR spectroscopy. The suppressive and curative models evaluated the antiplasmodial activity of dihydroartemisinin (DHA), quercetin, and its two synthesized derivatives. A similar administration design was adopted to determine the effects of quercetin and the two derivatives on the pharmacokinetics (PK) of DHA in albino rats. Blood was obtained from the hearts of the animals at 0.25, 0.5, 1, 2, 3, and 5 hours post-dose (n = 5 per time point). UV Spectrophotometer was used to analyse the concentration of DHA in the serum. The molecular docking studies of the synthesised compounds with 2ghu showed binding energy from -8.0 to -9.0 kcal/mol, with 3,5,7,3’,4′ -penta-acetoxyflav-3-ene (quercetin pentaacetate) and 3,3′,4′,5,7-pentahydroxyflavylium (cyanidin) having the best binding activity amongst other derivatives. Quercetin and the synthesized compounds exhibited a significant (p <0.05) suppressive and curative potential, with quercetin giving the highest parasitaemia clearance of 73.55 ± 3.06. There was a significant alteration of PK parameters of DHA by quercetin and the synthesized derivatives. The results confirm the antiplasmodial activity of quercetin and the synthesized quercetin derivatives.