An amine‐containing non‐interpenetrating pillar‐layer framework, [Zn2(dbtcb)(L1)]⋅x solvent (1), has been synthesized from Zn(NO3)2 and the ligands 1,4‐dibromo‐2,3,5,6‐tetrakis(4‐carboxyphenyl)benzene (H4DBTCB) and 2,5‐bis(4‐pyridyl)aniline (L1). The [Zn2(COO)4] secondary building units (SBUs) are bridged by DBTCB to form two‐dimensional layers that are linked by L1 ligands acting as pillars to form a three‐dimensional network. This NH2‐containing framework can undergo versatile tailoring through post‐synthetic covalent modification, solvent‐assisted linker exchange (SALE), and single‐crystal‐to‐single‐crystal (SC‐SC) transmetalation reactions. Acetamide‐functionalized [Zn2(L2)(dbtcb)]⋅xsolvent (2) could be obtained by direct synthesis from Zn(NO3)2, N‐acetyl‐2,5‐bis(4‐pyridyl)aniline (L2) and H4DBTCB. Importantly, compound 1 with pure NH2 ligands as pillars could be obtained by SALE of 2 with L1 in DMSO solution. The transmetalation reactions of 1 with CuII, NiII, and CoII were studied; inductively coupled plasma‐atomic emission (ICP) analysis revealed that 1 underwent almost complete SC‐SC transmetalation with CuII within 30 h, whereas with NiII and CoII only 70 and 80 % substitutions were achieved. Photoluminescence studies revealed that 1 and 2 display yellow‐green and UV emission, respectively, under a UV lamp. Furthermore, the photoluminescent properties could be tuned by introducing mixed pillar amino ligands L1 and L2 into the MOF to produce multivariate (MTV) MOF 3 displaying overall orange emission.