We describe here a new species of Casearia from Panama based on both morphological and molecular data. Casearia isthmicasp. nov. is restricted to the mid-elevation cloud forests of Central Panama and presents morphological similarities with two more widespread species, C. sanchezii from high elevation areas of El Salvador and Mexico and C. tremula from the Caribbean, Central America, and Northern South America. Casearia isthmica differs in presenting pedunculated and congested inflorescences with up to 20 flowers, as well as flowers with 12 stamens and a pubescent style. Phylogenetic analysis based on selected plastid (petD, trnK-matK, rpl16 and rps4-trnLF) and nuclear (GBSSI and ITS) markers shows that the new species belongs to subclade B3 of Casearia, a lineage that encompasses species from Central America, Mexico and the Caribbean. Results of the morphological and molecular analysis were congruent and allowed a broader understanding of this new taxon, especially regarding its relationships to other Casearia.