The systematics of Megalopodidae is not adequately known, in spite of it being a relatively small group of phytophagous beetles. The first phylogenetic analysis of Megalopodidae with a comprehensive generic representation (25 genera of 30 described, 10 subgenera and 77 species) is undertaken. A parsimony analysis under equal and implied weights was carried out based on 147 adult and larval morphological characters. Subfamilies Palophaginae and Zeugophorinae were recovered as monophyletic, by contrast with Megalopodinae, which proved to be paraphyletic. Atelederinae are proposed as a new subfamily. Also, three tribes and three subtribes within Megalopodinae are proposed: Leucasteini trib.n., Sphondyliini trib.n. and Megalopodini, the latter including Macrolophina subtrib.n., Temnaspidina subtrib.n. and Megalopodina. The genera Macrolopha, Kuilua, Poecilomorpha, Temnaspis, Antonaria, Agathomerus, Megalopus and Bothromegalopus were recovered as non-monophyletic. New delimitations of the polyphyletic genera Poecilomorpha and Macrolopha are proposed, Clythraxeloma is resurrected, and the subgenera of Agathomerus are suppressed. The following new combinations are proposed: Kuilua apicata (Fairmaire), K. nyassae (Jacoby), Poecilomorpha cribricollis (Pic), P. minuta (Pic), Clythraxeloma assamensis (Jacoby), C. bipartita (Lacordaeri), C. discolineata (Pic), C. downesii (Baly), C. gerstaeckeri (Westwood), C. laosensis (Pic), C. maculata (Pic), C. mouhoti (Baly), C. nigrocyanea (Motschulsky), C. pretiosa (Reineck), Temnaspis tricoloripes (Pic) and Barticaria faciatus (Dalman). Clythraxeloma cyanipennis Kraatz is a restored combination. Distribution patterns of Megalopodidae largely conform to the breakup of Gondwanaland, with its main clades having particular distributions: Andean-Australian (Palophaginae), Ethiopian (Leucasteini, Sphondyliini, and Macrolophina), Neotropical (Ateledrinae and Megalopodina) and Ethiopian-Oriental-Palaearctic (Temnaspidina the result of a secondary expansion. Zeugophorinae present a worldwide distribution, except for the Neotropical and Andean regions, which may be the result of geodispersal. The findings of the present study also shed light on groups with taxonomic issues, where phylogenetic analyses are strongly needed.