Photochemical [2+2]-photocycloadditions are used to efficiently access strained organic molecular architectures, storing solar energy in chemical bonds. Functionalized -ladderenes have been shown to undergo [2+2]-photocycloadditions to afford cubanes, an energy-dense class of organic molecules. The substituents (e.g., methyl, trifluoromethyl, and cyclopropyl) affect the overall reactivities of these cubane precursors leading to a yield from 1% to 48%. We now integrate single and multireference calculations and our machine-learning-accelerated non-adiabatic molecular dynamics (ML-NAMD) to understand how substituents affect the mechanistic photodynamics of [2+2]-photocycloadditions. Our calculations show that steric clashes destabilize the 4π-electrocyclic ring-opening pathway and minimum energy conical intersections by 0.72–1.15 eV and reaction energies by 0.68–2.34 eV. In contrast, favorable dispersive interactions stabilize the [2+2]-photocycloaddition pathway, lower the conical intersection energies by 0.31–0.85 eV and cubane reaction energies by 0.03–0.82 eV. The 2 ps ML-NAMD trajectories reveal that closed-shell repulsions block a 6π-conrotatory electrocyclic ring-opening pathway with increasing steric bulk. 57% of the methyl-substituted -ladderene trajectories proceed through the 6π-conrotatory electrocyclic ring-opening, whereas the trifluoromethyl- and cyclopropyl-substituted 3-ladderenes chemoselectively proceed through [2+2]-photocycloaddition pathways. The predicted cubane yields (H: 0.4% < CH3: 1% < CF3: 14% < cPr: 20%) match the experimental trend; these substituents pre-distort the reactants to resemble the conical intersection leading to cubane.