Here, we provide the first quantitative analysis of quantum-size-controlled photocatalytic H₂ evolution at the semiconductor–solution interface. We find that the hydrogen evolution rate from suspended mercaptoethanol-ligated CdSe quantum dots in aqueous sodium sulfite solution depends on nanocrystal size. Photoelectrochemical measurements on CdSe nanocrystal films reveal that the observed reactivity is controlled by the free energy change of the system, as determined by the proton reduction potential and the quasi-Fermi energy of the dots. The corresponding free energy change can be fitted to the photocatalytic activity using a modified Butler–Volmer equation for reaction kinetics. In parallel, Surface photovoltage spectroscopy (SPS) was used to photochemical charge transfer at the CdSe quantum dot -indium doped tin oxide (ITO) interface. Negative photovoltages are observed under super band gap illumination from majority carrier (electron) injection into the ITO substrate. The photovoltage onset energies track the optical band gaps of the samples and are assigned as effective band gaps of the films. The photovoltage values (−125 to −750 mV) vary with quantum dot sizes and are modulated by the built-in potential of the CdSe–ITO Schottky type contacts. Deviations from the ideal Schottky model are attributed to Fermi level pinning in states approximately 1.1 V negative of the ITO conduction band edge. Positive photovoltage signals of +80 to +125 mV in films of >4.0 nm nanocrystals and in thin (70 nm) nanocrystal films are attributed to electron–hole (polaron) pairs that are polarized by a space charge layer at the CdSe–ITO boundary. The space charge layer is 70–150 nm wide, based on thickness-dependent photovoltage measurements. These findings establish a quantitative experimental basis for quantum-confinement-controlled proton reduction and electron transfer with semiconductor nanocrystals.