New 1,3,4-trisubstituted pyrazole derivatives were synthesized and evaluated for their antiplasmodial activity. Compounds 4b, 4c, 7a and 7d were the most potent antiplasmodial agents against P. berghei with percent of suppression ranging from 90 to 100%. They were also screened for their in vitro antimalarial activity against the chloroquine resistant strain P. falciparum, (RKL9). Compound 4c displayed the highest in vitro antimalarial activity; 13-fold higher than standard chloroquine phosphate. Molecular docking of the most active compounds against the wildtype and quadruple mutant pf DHFR-TS structures rationalized the in vitro antimalarial activity. Furthermore, these compounds exhibited reasonable in silico drug-likeness and pharmacokinetic properties. Toxicity studies of the most active compounds revealed that all tested compounds were non-toxic and well-tolerated up to 150 mg/kg via oral route and 75 mg/kg via parentral route. According to RBC hemolysis assay, it was found that compound 7a was the most potent anti-inflammatory and least toxic derivative with IC<sub>50</sub> value 71-fold higher than IC<sub>50</sub> value related to the antimalarial activity. Moreover, cytotoxicity assessment revealed that compound 4c was the least toxic derivative with IC<sub>50</sub> value 70000-fold higher than IC<sub>50</sub> value related to the antimalarial activity.