Chemistry of the polyamide active layer of a desalination membrane is critical in determining both its physical and chemical properties. In this study, we designed and fabricated three novel membranes with different active layers using the crosslinkers: terephthaloyl chloride, isophthaloyl chloride, and trimesoyl chloride. The crosslinkers were reacted with an aqueous solution of an aliphatic tetra-amine. Because these crosslinkers differ in their structures and crosslinking mechanisms during interfacial polymerization, the resultant membranes also possess different structural properties. The water contact angle of the fabricated membranes also varies; the water contact angles of 4A-3P-TPC@PSF/PET, 4A-3P-TMC@PSF/PET, and 4A-3P-IPC@PSF/PET, are 68.9°, 65.6°, and 53.9°, respectively. Similarly, the desalination performance of resultant membranes also showed variations, with 4A-3P-TPC@PSF/PET, 4A-3P-IPC@PSF/PET, and 4A-3P-TMC@PSF/PET having a permeate flux of 17.14, 25.70, and 30.90 L·m⁻²·h⁻¹, respectively, at 2.5 MPa. The 4A-3P-TPC@PSF/PET membrane exhibited extensive crosslinking with aliphatic linear amine, and cationic dye rhodamine B, MgCl₂, and amitriptyline rejection rates of 98.6%, 92.7% and 80.9%, respectively. The 4A-3P-TMC@PSF/PET membrane showed mediocre performance, while 4A-3P-IPC@PSF/PET membrane showed even lower performance, with a 35% rejection of methyl orange dye.