Manfreda santana-michelii is described from ecotone areas between open pine-oak forest and savannoid vegetation in the northern range of the Sierra Madre del Sur, in western Mexico. Morphologically, the new species resembles M. involuta and M. singuliflora, but differs from both of these by the development of denticulate margins on the leaves, racemose inflorescences, two pedicellate, tubulate, ascending flowers per node, a straight perigone tube, and 0.3–0.5 cm long filaments that are inserted just at the base of the perigone lobes. Illustrations, photographs for the new species and similar taxa, and a key to identify Manfreda in western Mexico accompany the description.