A comprehensive analysis of published records of terrestrial vascular plants reported from the Comino archipelago (Maltese Islands) since the mid-1800s and of plants recorded by us between 2008 and 2025 was combined to synthesise the first annotated and comprehensive checklist of vascular plants of Comino. A total of 328 observations were made, of which 78 are new records for Comino and two are recorded for the first time in the Maltese Islands. The flora consists of 490 vascular plant species. This study identifies and examines ecologically sensitive species on the Comino archipelago, including 58 strictly and legally protected species, 21 endemics, and several other plants that are red-listed as threatened species or are very rare in the Maltese Islands (e.g., Euphorbia peplis, Hornungia procumbens, and Malva setigera). Alien species are also reviewed, and 12 out of the 61 recorded species are declared invasive for Malta, but only a few are effectively invasive on Comino (e.g., Acacia saligna, Ailanthus altissima, and Oxalis pes-caprae). In addition, this account offers a concise yet comprehensive overview of Comino's geology, natural habitats, climate, and anthropogenic history. More critically, it identifies the principal threats and pressures affecting the island, which have contributed, at least in part, to the disappearance of approximately 160 species previously recorded but not observed for several decades. As highlighted in previous studies, the persistent issue of over-tourism on Comino over the past 15–20 years warrants urgent attention, as the most recent reports indicate that some 10,000 visitors flock to the small beaches of the Blue Lagoon and Santa Marija Bay, which, as also demonstrated in this report, overwhelm and disturb this ecologically sensitive Natura 2000 archipelago.