The arid Central Gulf Coast ecoregion, characterized mainly by sarcocaulescent scrub, is a poorly studied area. This paper addresses this knowledge gap with an annotated checklist of the vascular plants of the Mulegé area (Bahía Concepción to Punta Chivato; 397 km²), which was compiled over at least 267 field days during 15 field seasons between 2003 and 2019. The inventory presents 411 taxa (330 species, 81 infraspecies) in 82 families and 288 genera. There are 342 taxa native to the peninsula, of which 78 are endemic or near-endemic taxa. Six species are included on Mexico's protected species list (NOM-059) and two are on the IUCN Red List. The extensive loss of the mangrove thickets along the Mulegé estuary and the rapid spread of the invasive species Cenchrus ciliare L. (Poaceae) are immediate ecological concerns compounded by the more long term effects of climate change, sea level rise and development. While this study shares up to 74% of families and 66% of the genera of several other regional floras for the peninsula, at the species level it shares between just 23% and 63% with them, highlighting Mulegé's local floristic diversity.