Osmolytes' mechanism of protecting proteins against denaturation is a longstanding puzzle, further complicated by complex diversities inherent in protein sequences. An emergent approach in understanding the osmolytes' mechanism of action toward biopolymer has been to investigate osmolytes' interplay with hydrophobic interaction, the major driving force of protein folding. However, the crucial question is whether all of these protein-stabilizing osmolytes display a single unified mechanism toward hydrophobic interactions. By simulating the hydrophobic collapse of a macromolecule in aqueous solutions of two such osmoprotectants, glycine and trimethyl N-oxide (TMAO), both of which are known to stabilize protein's folded conformation, we here demonstrate that these two osmolytes can impart mutually contrasting effects toward hydrophobic interaction. Although TMAO preserves its 2 protectant nature across diverse range of polymer-osmolyte interactions, glycine is found to display an interesting crossover from being a protectant at weaker polymer-osmolyte interactions to being a denaturant of hydrophobicity at stronger polymer-osmolyte interactions. A preferential-interaction analysis reveals that a subtle balance of conformation-dependent exclusion/binding of osmolyte molecules from/to the macromolecule holds the key to overall heterogenous behavior. Specifically, TMAOs' consistent stabilization of collapsed configuration of macromolecule is found to be a result of TMAOs' preferential binding to polymers via hydrophobic methyl groups. However, polar glycine's crossover from being a protectant to denaturant across polymer-osmolyte interaction is rooted in its switch from preferential exclusion to preferential binding to the polymer with increasing interaction. Overall, by highlighting the complex interplay of osmolytes with hydrophobic interaction, this work puts forward the necessity of quantitative categorization of osmolytes' action in protein.