We computationally investigate the utility of molecular junctions to probe chemical reactivity at the single-molecule limit. To do so, we employ molecular dynamics (MD) coupled to quantum transport simulations to investigate the classic Diels–Alder reaction but in the context of nanoscale junctions where the reactants are nanoconfined and the reactive pair is mechanically brought to proximity. To capture reactive events, the MD employs the density functional tight binding method to account for interatomic interactions. To understand the thermodynamic driving forces behind the reaction in this novel chemical environment, we reconstruct the potential of mean force along the reaction coordinate and decompose it into energetic and entropic contributions. The analysis demonstrates that the process is entropically penalized, which makes the reaction barrier sensitive to changes in the temperature and reactant rigidity. The simulations further show that in nanojunctions the degree of reactivity can be mechanically manipulated simply by controlling the proximity of the electrodes. Surprisingly, for optimal electrode separations, the entropic and energetic cost in the nanoconfined reaction coincides with that observed in bulk, establishing a clear connection between measurements performed in these two vastly different reactive environments. Finally, we show how conductance measurements can be used to experimentally monitor the process at the single-entity limit.