The effects of thioamide incorporation into N, N-dimethyl-2-( N-methylacetamido)acetamide and N-methyl-2-( N-methylacetamido)acetamide as the simplest models of a dipeptoid structure and a peptoid-peptide hybrid are discussed. The solvent-modulated conformational features of model compounds were examined by computations enhanced by natural bond orbital (NBO) analysis and experimentally by kinetic and equilibrium measurements using NMR spectroscopy. The computations supported by NBO analysis showed that intrinsic stability of the predominant trans isomer (αD and C7β forms) of the dipeptoid model results from an indirect n → π* interaction, occurring between the carbonyl oxygen lone pair ( n) and the π* orbital of the adjacent amide carbonyl through the C-H antibond (σ*). The direct n → π* interaction constitutes a negligible contribution to trans stabilization. The N-terminal thioxo substitution increases this indirect electron delocalization, making the αD isomer prevalent. The nX → σN'C-H* interaction is an additional source of stability of the trans-C7β form relevant for the underivatized dipeptoid model and its C-terminal thioamide counterpart. In the peptoid-peptide hybrid, the trans preference is perturbed by subtle differences in the H-bond donor-acceptor abilities between the thioxo and oxo groups. The cis isomer becomes more populated with an increase in the strength of polarity and the hydrogen bonding acceptor ability of the solvent molecules. While thioxo substitution slightly shifts the trans- cis equilibrium in polar solvents, it effectively allows for increasing or decreasing the barrier to trans- cis rotation with respect to underivatized model compounds depending on N- vs C-terminal thioamide backbone substitution.