The Mirandea clade (Acanthaceae) is part of the Tetramerium lineage (Acanthaceae: Justicieae). Traditionally, macromorphological floral traits such as floral form and color have guided taxonomy in the Tetramerium lineage but earlier results on this group indicate that these traits are highly homoplastic. The present study includes all described species and multiple samples of Hoverdenia, Mirandea, and Yeatesia to fully delimit the Mirandea clade, test monophyly of species, and determine relationships among them using DNA sequence data from five regions (nuclear: nrITS and ncpGS; cp: trnS—G, ndhF—trnL_(UAG), and trnT-L). The Mirandea clade is here shown to include seven species currently placed in four genera: Mirandea, Hoverdenia, Yeatesia, and Justicia. The lineage is edaphically and geographically cohesive, occurring along the Sierra Madre Oriental in Mexico and southern Texas in xeric habitats, except for one species that inhabits a broad geographical region of the southeastern U. S. A. in mesic habitats. We present micromorphological data from seeds and pollen and discuss the evolution of these traits, as well as other floral traits. These results support the heterodox idea that micromorphological traits of seed testa and pollen exine, morphologies that are not found among other clades of the Tetramerium lineage, are phylogenetically informative among members of the Mirandea clade whereas floral traits are not. Plants in this clade exhibit remarkable interspecific variation in both floral form and color, suggesting divergent evolution in conjunction with pollination syndrome. Taxonomic implications of these results are discussed.