During neuroinflammation, the microglia tend1 to produce excess amounts of pro-inflammatory mediators. This results in neuronal apoptosis and death. Studies have established a link between neuroinflammation and the pathogenesis of some viral infections and cerebral malaria (CM) thus providing reliable targets for treating these CNS conditions. Research suggests that the artemisinin and its derivatives are used as ‘precursors’ for antimalarial drugs and have also been proposed to have anti-inflammatory properties. This study therefore aimed to evaluate the modulation of neuroinflammation by artemisinin and its derivatives (artesunate and artemether) in polyinosinic: polycytidylic acid [(Poly (I:C)] and synthetic hemozoin (sHZ)-activated BV-2 microglia. Cultured BV-2 microglia cells were pre-treated with artemisinin (1.25, 2.5, 5 and 10 µM), artesunate (0.025, 0.05, 0.1 and 0.2 µM) or artemether (1.25, 2.5, 5 and 10 µM). This was followed by stimulation with either Poly (I:C) (20 µg/mL) or sHZ (400 µg/mL). The levels of nitrite in culture supernatants were measured using the Griess assay, while the production of pro-inflammatory cytokines IL-6, IL-1β and TNF-α were measured using mouse ELISA kits. Protein expressions of phosphorylated IκB and NF-κB-p65 sub-units were also determined using ELISA. Western blotting was used to determine protein levels of iNOS, phospho-p38 MAPK, phospho-pJNK, caspase-1 and NLRP3 inflammasome. Transient transfection and luciferase reporter gene assay were used to determine the effects of drugs on NF-κB-mediated gene expression. Results showed that artemisinin, artesunate and artemether reduced the elevated production of IL-6, IL-1β and TNF-α following stimulation of cultured BV-2 microglia with Poly (I:C) and (sHZ). Further, results showed that these drugs decreased iNOS protein expressions and inhibited NO production in activated microglia. Results of experiments involving Poly (I:C)-induced neuroinflammation in BV-2 cells also revealed that artemisinin, artesunate and artemether inhibited NF-κB signalling by significantly reducing phosphorylation of IκB and p65, as well as DNA binding and transactivation of NF-κB. Western blot results also showed that all drugs investigated inhibited p38 but not JNK MAPK activation in Poly (I:C)-stimulated BV-2 microglia. In sHZ-stimulated microglia, both artemisinin and artesunate, but not artemether reduced protein levels of caspase-1 and NLRP3 inflammasome, while reducing the activity of caspase-1.It is proposed that artemisinin, artesunate and artemether inhibit neuroinflammation in BV-2 microglia stimulated with either Poly (I:C) or sHZ. It is also suggested that these drugs modulate neuroinflammation through mechanisms involving NF-κB and p38 MAPK activation in Poly (I:C) activated microglia while targeting the NLRP3 inflammasome/caspase-1 signalling in sHZ-activated microglia cells. Consequently, these drugs have the potential to be re-purposed as adjuncts in the treatment of CNS conditions like viral infection and cerebral malaria-mediated neuroinflammation.