Growth dynamics and bioactivity variation of the Mediterranean demosponges Agelas oroides and Petrosia ficiformis were investigated over 15 months at Paraggi and Colombara within the Marine Reserve of Portofino Promontory (Mediterranean Sea, Ligurian Sea, Italy). For both species, growth rates varied between individuals and were unaffected by initial sponge size. The two species showed a different trend in growth pattern: A. oroides did not vary significantly between seasons, sites and depths; in contrast, some individuals of P. ficiformis showed a seasonal pattern, shrinking during winter as water temperature decreased and growing during summer when water temperature increased. Differences in growth between the two species may result from different reproductive cycles, food availability, species‐specific thermophily and patterns of spatial competition. Moreover, spatial competition probably induced sponges to produce bioactive secondary molecules. Spatial and temporal variation of bioactivity of both species was examined for the first time by studying its effect on human neuroblastoma cells. The bioactivity of A. oroides extracts differed significantly between seasons, sites and depths, whereas the cytotoxicity of P. ficiformis differed significantly between seasons and depths (differences for sites were not determined). These results suggest the possible influence of environmental factors on bioactive metabolite biosynthesis.