The effects of catalyst on the molecular weight, chemical structure, and yellowness of isosorbide-based polycarbonate (ISB-PC) in the melt-transesterification and polycondensation stages were investigated. Results showed that the high steric hindrance and intramolecular hydrogen bonding of the endohydroxyl group (endo-OH) of ISB enabled its reactivity to be lower than that of the exohydroxyl group (exo-OH). We also found that the reactivity of endo-OH with Biphenyl carbonate can be preferentially activated by strong electrophilic catalysts, and that the configuration of the ISB-PC chain strongly depended on the reactivity balance between endo-OH and exo-OH. Various catalysts with different coordinate capacities, acidity coefficients, and radius of metal ion were further tested. Catalysts with a calcium or zinc ion showed a higher reactivity of endo-OH than exo-OH, resulting in a high glass-transition temperature of ISB-PCs. Results suggested as well that the thermal stability of ISB-PC may be correlated to the amount of OH groups at the chain ends, whereas its yellowness mainly arose from 1,4-sorbitan due to the hydrolysis of ISB.