In the present study, we have carried out extensive General Unrestricted Structure–Activity Relationships, conventional 3D-Quantitative Structure–Activity Relationships, and CoMFA analyses of synthetic prodiginines displaying moderate to high activities against Plasmodium Falciperum. 2D and 3D descriptors, various statistical parameters viz. R2, R2adj, standard error, Y-randomization, etc., were checked to build fruitful 3D-Quantitative Structure–Activity Relationships model. The best five parametric 3D-Quantitative Structure–Activity Relationships model is with R2 = 0.924 and R2pred = 0.901. CoMFA was performed to check the electrostatic and steric regions, which affect the activity. The CoMFA model is graphically inferred using contour plots, which provide insight into the structural requirements for increasing the activity of a compound. The General Unrestricted Structure–Activity Relationships model, with R2 = 0.940 and Q2 = 0.912, suggests that the presence of F on aromatic ring is good for activity. The analyses reveal that lipophilicity plays a crucial role in deciding the activity for these molecules.