Metal-organic frameworks (MOFs) exhibit significant potential for mitigating carbon emissions due to their high porosity and tunability. Despite numerous reports on CO2 capture by MOF sorbents, a common challenge is their poor selectivity for CO2 over water. Moreover, in-depth studies are much needed to elucidate the relationships among the pore surface structure, hydrophobicity, and CO2 uptake capacity/selectivity. In this work, we investigate the factors influencing CO2 adsorption capacity and selectivity under humidity in a series of isoreticular pillar-layer structures, Ni2(L)2(dabco) (L = bdc, ndc, adc). Our study shows that increasing ligand conjugation not only results in increased hydrophobicity, decreased pore size and BET surface area, but also leads to the change of primary binding sites of water molecules and higher binding energy of CO2, all of which contribute to largely increased CO2 uptake capacity under humid conditions. Additionally, increasing ligand conjugation and consequently hydrophobicity slow down and reduce competitive water adsorption drastically. Notably, the MOF made of ligand with the highest conjugation, Ni2(adc)2(dabco), exhibits significantly enhanced CO2 adsorption in N2/CO2 binary mixtures under relatively high humidity (50% RH), with an increase of ∼31% and ∼36% for the composition of 15/85 and 50/50, respectively, compared to dry conditions. An experimental FTIR study and DFT theoretical calculations confirm that H2O occupies different primary binding site in Ni2(bdc)2(dabco) and Ni2(adc)2(dabco), and under humid conditions a higher binding energy of CO2 is achieved with preferential H2O/CO2 co-adsorption in Ni2(adc)2(dabco), potentially creating additional adsorption sites for CO2