Recent observations suggest that some high-velocity clouds may be confined by massive dark matter halos. In particular, the proximity and proposed dark matter content of the Smith Cloud make it a tempting target for the indirect detection of dark matter annihilation. We argue that the Smith Cloud may be a better target than some Milky Way dwarf spheroidal satellite galaxies and use γ-ray observations from the Fermi Large Area Telescope to search for a dark matter annihilation signal. No significant γ-ray excess is found coincident with the Smith Cloud, and we set strong limits on the dark matter annihilation cross section assuming a spatially extended dark matter profile consistent with dynamical modeling of the Smith Cloud. Notably, these limits exclude the canonical thermal relic cross section (∼ 3 × 10−26 cm3 s−1) for dark matter masses ≲ 30 GeV annihilating via the ��¯ or τ+τ− channels for certain assumptions of the dark matter density profile; however, uncertainties in the dark matter content of the Smith Cloud may significantly weaken these constraints.