Mediterranean marine biota suffers from various anthropogenic threats. Among them, pollutants such as mercury (Hg) represent important environmental issues that are exacerbated by bioaccumulation and bioamplification along food webs via its organic form, monomethylmercury (MMHg). To date, very little is known regarding the impact of mercury on Porifera and the few available studies have been exclusively focused on Demospongiae. This work studies the effect of MMHgCl at different biological levels of Oscarella lobularis (Porifera, Homoscleromorpha). Bioaccumulation assays show that MMHgCl significantly accumulated in sponge tissues after a 96-h exposure to 0.1 μg L−1. Toxicity assays (LC5096h) show a sensibility that depends on life-stage (adult vs bud). Additionally, we show that the exposure to 1 μg L−1 MMHgCl negatively impacts the epithelial integrity and the regeneration process in buds, as shown by the loss of cell-cell contacts and the alteration of osculum morphogenesis. For the first time in a sponge, a whole set of genes classically involved in metal detoxification and in antioxidant response were identified. Significant changes in catalase, superoxide dismutase and nuclear factor (erythroid-derived 2)-like 2 expressions in exposed juveniles were measured. Such an integrative approach from the physiological to the molecular scales on a non-model organism expands our knowledge concerning sensitivity and toxicity mechanisms induced by MMHg in Porifera, raising new questions regarding the possible defences used by marine sponges.