This article reports single-grain multi-elemental results (Sr, Y, Th, U, and rare earth elements) obtained in 966 apatites from 18 rocks (sandstones and granitoids) that were sampled from the Mesozoic (Todos Santos and San Ricardo Formations) and Eocene (the El Bosque Formation) successions as well as from the Permian–Triassic Chiapas Massif Complex (CMC), all of which are exposed within the Sierra de Chiapas (SCH), SE Mexico. The objectives of the present study are (1) to establish changes in provenance between the Mesozoic and Eocene sedimentary sequences using single-grain apatite geochemistry, and (2) to identify source areas for siliciclastic materials from the Todos Santos, San Ricardo, and the El Bosque Formations. The results of the present work strongly suggest that apatites from the Todos Santos and San Ricardo Formations were mainly derived from intermediate to felsic I-type granitoids as well as from arc-related volcanic rocks, indicating that the CMC basement was the most important source area for the Mesozoic sandstones in the SCH. An abrupt change in provenance from Mesozoic to Eocene units was identified based on single-grain apatite geochemistry. Detrital apatites of the Ypresian–Lutetian El Bosque Formation were derived from diverse source rocks such as mafic–ultramafic rocks, intermediate to felsic I-type plutons, strongly fractionated S-type granites and pegmatites, as well as from different metamorphic source lithologies (including high-pressure rocks) such as gneisses, migmatites, metapelites, and/or eclogites. It was proposed, therefore, that most Eocene sediments of the SCH were derived from the Guatemala Suture Complex, which involves all the rock types mentioned above. A minor portion of the El Bosque Formation sediments was derived from the CMC area and/or from recycled sandstones from the Mesozoic Todos Santos and San Ricardo Formations. Some advantages and disadvantages of provenance studies based on detrital apatite chemistry were also observed and briefly discussed.