The generation of singlet oxygen (1O2) has been established as the principal mechanism of photodynamic therapy (PDT). Various dyes, metal nanoparticles, and clusters have been shown to sensitize 1O2. However, metal nanoclusters are even more promising candidates as photosensitizers for this purpose. By understanding the optical properties that lead to efficient 1O2 generation, one can fully realize their potential as PDT photosensitizers. Three different metal nanoclusters, Au25, Ag32, and Au144, are investigated for their 1O2 generation efficiency. The Au144 showed a 1O2 generation rate that is 2 orders of magnitude higher than that for Au25 and Ag32, and several orders of magnitude higher than nanoparticles (>5 nm) due to Au144's high absorption cross section-to-volume ratio. The effectiveness of PDT in live cells with nanoclusters was demonstrated by two-photon excitation compared to one-photon excitation. The implication of these results points toward new efficient two-photon 1O2 sensitizers for photodynamic therapy.