Since 2010, a bottom-up initiative has been launched in Santorini Island (Aegean Sea, Eastern Mediterranean) for the establishment of the first fully-protected marine protected area in the Cyclades, aiming at improving fisheries and enhancing responsible recreational uses at sea. Following discussions with local small-scale fishers and divers, two sites along the southern and southeastern coasts of the island were suggested as suitable to this end. In 2012, a baseline study was conducted at these areas to assess their state and provide an ecological snapshot that would enable sound designation and monitoring. Several ad hoc indices and metrics were applied, taking into account structural and functional features of the upper infralittoral algae and Posidonia oceanica beds. An integrated assessment of the infralittoral fish assemblages and their associated benthic communities was also performed. Our most important findings were: (i) the low total fish biomass and the absence of adult top predators, indicating overfishing; (ii) the overgrazing effects of the overabundant alien herbivore spinefoot fishes (Siganus spp.), as reflected by the abnormal structure of the algal communities; (iii) the scarcity of signs of pollution or other direct anthropogenic pressures, as indicated by the good environmental status of the P. oceanica meadows and the upper infralittoral vegetation; and (iv) the presence of a rich diversity of species and habitats, especially along the Akrotiri Peninsula and the wider volcanic Caldera. These findings provide useful insights on strengths and weaknesses of the study area and are discussed together with their implications for protection and management.