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Essential plasmodial kinases Pf GSK3 and Pf PK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual Pf GSK3/ Pf PK6 inhibitor active against blood stage Pf 3D7 parasites. To establish structure-activity relationships for Pf PK6 and Pf GSK3, 52 analogues were synthesized and assessed for the inhibition of Pf GSK3 and Pf PK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual Pf GSK3/ Pf PK6 inhibitors 23d ( Pf GSK3/ Pf PK6 IC 50 = 172/11 nM) and 23e ( Pf GSK3/ Pf PK6 IC 50 = 97/8 nM) with antiplasmodial activity ( 23d Pf 3D7 EC 50 = 552 ± 37 nM and 23e Pf 3D7 EC 50 = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual Pf PK6/ Pf GSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.