To assess the impact of two plastic derived chemicals: bisphenol A (BPA) and the di-2-ethylhexyl phthalate (DEHP), on phytoplankton biomass and community structure, microcosm incubations were performed during spring and summer, with offshore and lagoon waters of a south-western Mediterranean ecosystem. Phytoplankton were exposed to an artificial mixture of BPA and DEHP and to marine water previously enriched with plastic-derivative compounds, originated from in situ water incubations of plastic debris for 30 days. After 96 h of incubation, changes were observed in phytoplankton biomass in the contaminated microcosms, with a net decrease (up to 50% of the control) in the concentration of Chlorophyll a in offshore waters. Concomitantly, plastic-derivative contamination provoked structural changes, especially for offshore waters. This suggests a relative tolerance of the lagoon communities to BPA and DEHP contamination, related to the dominance of Chaetoceros spp., which could potentially be used as a bioindicator in bioassessment studies.