Sugar puckering of nucleosides impacts nucleic acid structures; hence their biological function. Similarly, nucleoside-based therapeutics may adopt different conformations affecting their binding affinity, DNA incorporation, and excision rates. As a result, significant efforts have been made to develop nucleoside analogues adopting specific conformations to improve bioactivity and pharmacokinetic profiles of the corresponding nucleoside-containing drugs. Understanding and ultimately predicting these conformational preferences would significantly help in the design of more effective structures. We report herein a computational study based on hybrid QM/MM umbrella sampling simulations that allow the accurate prediction of the sugar conformational preferences of chemically modified nucleosides in solution. Moreover, we pair these simulations with natural bond orbital (NBO) analysis to gain key insights into the role of substituents in the conformational preferences of these nucleosides.