Development of 2, N⁶-disubstituted 1,2-dihydro-1,3,5-trizine-4,6-diamines derivatives were carried out by quantitative structure–activity relationship (QSAR) analyses. The nature of the substituent(s) on C-2; the nature of the substituent(s) on the distal aryl ring; as well as the nature and length of the flexible tether between the rings, to find out the structural requirements of their antimalarial activities against cycloguanil resistant (FCR-3) Plasmodium falciparum strain and sensitive to pyrimethamine. The statistically significant best 2D QSAR models for FCR-3, having correlation coefficient (r²) = 0.9821 and cross validated squared correlation coefficient (q²) = 0.6471 were developed by multiple linear regression stepwise (SW–MLR) forward algorithm. The results of the present study may be useful on the designing of more potent analogues as antimalarial agents.