Plasmodium falciparum protein kinase 7 (PfPK7) is an important drug target for the development of anti-malarial treatment. In this study, hologram quantitative structure-activity relationship (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of imidazopyridazine derivatives of PfPK7 inhibitors. The best HQSAR model was obtained using atoms, connection, donor, and acceptor as fragment distinction parameter with fragment size (4-7) using a hologram length of 353 and 6 components (q 2 = 0.770, r 2 = 0.964). The receptor-guided alignment has produced better statistical results for both CoMFA (q 2 = 0.590, r 2 = 0.986) and CoMSIA (q 2 = 0.735, r 2 = 0.988). The predictive ability of the developed models was further validated by a test set of eight compounds. HQSAR contribution map identified the presence of phenyl ring and cyclohexane moiety makes positive contribution for activity. Furthermore, CoMFA and CoMSIA contour maps suggested that additional bulky groups in cyclohexane moiety would increase the biological activity of PfPK7 inhibitors. Finally, these QSAR models were used to design new virtual molecules for imidazopyridazine derivatives and the results obtained from this study could be useful for further investigations.