Recent extinction rates suggest that humans are now causing the sixth mass extinction, and the Mediterranean islands are at the forefront of many of the environmental issues involved. This study provides an alternative approach for investigating documented local plant extinctions that occurred in Sardinia (western Mediterranean) during the last half century. A total of 190 local extinctions of 62 plant species were used to investigate the independent effects of eight ecological and anthropogenic variables and to model the areas of potential extinctions where plant conservation efforts could be focused. If all analysed plant species were considered together, ecological factors explained local extinctions more than anthropogenic factors. The independent effects of each factor considerably varied among species of different lifeforms and altitude ranges. Accordingly, distribution models of local extinctions outscored areas that are potentially rich in plant species with conservation interest, but which are particularly affected by humans. This paper suggests a reproducible, operational framework for analysing which extinction factors may play important roles in similar contexts and where they might be relevant.