Research Highlights: The effects of climate change on habitat loss, range shift and/or genetic impoverishment of mid-elevation plants has received less attention compared to alpine species. Moreover, genetic diversity patterns of mountain forest herbaceous species have scarcely been explored in the Balkans. In this context, our study is the first that aims to examine Helleborus odorus subsp. cyclophyllus, a medicinal plant endemic to the southern part of the Balkan Peninsula. Background and Objectives: We compare its genetic diversity and structure along the continuous mountain range of western Greece with the topographically less structured mountains of eastern Greece, and predict its present and future habitat suitability, using several environmental variables. Materials and Methods: Inter Simple Sequence Repeat (ISSR) markers were used to genotype 80 individuals from 8 populations, covering almost the species’ entire distribution range in Greece. We investigated the factors shaping its genetic composition and driving its current and future distribution. Results: High gene diversity (0.2239–0.3319), moderate population differentiation (0.0317–0.3316) and increased gene flow (Nm = 1.3098) was detected. According to any GCM/RCP/climate database combination, Helleborus odorus subsp. cyclophyllus is projected to lose a significant portion of its current distribution by 2070 and follow a trend towards genetic homogenization. Conclusions: Populations exhibit in terms of genetic structure a west–east genetic split, which becomes more evident southwards. This is mainly due to geographic/topographic factors and their interplay with Quaternary climatic oscillations, and to environmental constraints, which may have a negative impact on the species’ future distribution and genetic composition. Pindos mountain range seems to buffer climate change effects and will probably continue to host several populations. On the other hand, peripheral populations have lower genetic diversity compared to central populations, but still hold significant evolutionary potential due to the private alleles they maintain.