Periodic　density　functional　theory　calculations　have　been　performed　to　investigate　the　structures,　the　linear　and　second　order　nonlinear　optical　(NLO)　properties　of　Zr-based　UiO-66　metal-organic　frameworks,　in　which　the　1,4-benzene-dicarboxylate　(BDC)　linkers　are　functionalized　by　a　series　of　isovalent　substituents　including　-NH2,　-OH,　-SH,　and　halogen　atoms.　Our　results　show　that　the　mixed　phase　will　be　formed　for　the　case　of　the　incorporation　of　a　single　hydroxyl　or　halogen　atom,　while　it　is　more　likely　to　synthesize　the　pure　phase　for　the　homodifunctionalized　compounds.　The　ligand　functionalization　results　in　the　appearance　of　the　band　gap　states　as　well　as　the　narrowing　of　the　band　gap.　For　the　linear　optical　response,　besides　the　redshift　of　the　absorption　edge,　the　ligand　modification　tends　to　increase　the　dielectric　constant　and　enhance　the　optical　anisotropy　of　UiO-66,　especially　when　two　-SH　groups　are　incorporated　into　the　BDC　ligand.　With　regard　to　the　NLO　activity,　the　second　harmonic　generation　(SHG)　intensity　of　the　pristine　UiO-66　is　comparable　to　that　of　KDP.　The　SHG　response　of　UiO-66　can　be　effectively　improved　by　the　single-site　substitution,　and　the　obvious　enhancement　of　the　SHG　activity　is　observed　after　introducing　the　sulfydryl　group　or　the　iodine　atom.　However,　it　is　noted　that　the　difunctionalizations　by　two　-OH　and　-SH　have　a　relatively　weak　impact　on　the　SHG　intensity　because　of　the　nearly　centrosymmetric　organization　of　the　homodifunctionalized　organic　linkers.　Among　all　derivatives,　UiO-66-(SH)2　is　the　most　promising　candidate　for　use　as　a　near-infrared　NLO　material　with　a　strong　SHG　effect　(＞20　pm/V)　and　good　phase　matchability.　Furthermore,　the　primary　origin　of　the　SHG　response　for　UiO-66　and　its　derivatives　is　determined　by　analyzing　the　band　structure.　This　study　reveals　the　possibility　of　designing　NLO　materials　with　outstanding　performances　based　on　the　UiO-66-derived　MOFs　through　rational　functionalization　of　the　organic　linking　unit.　Copyright　©　2020　American　Chemical　Society.