The Thau lagoon is a Mediterranean coastal lagoon used for shellfish farming. It is periodically affected by anoxia events that trigger oyster mortality. To investigate the effects of an anoxia event focussed on nutrient dynamics and the responses of the microbial planktonic communities a 13-day in situ experiment was performed in September 2020. Transparent mesocosms (270 L) were placed at a depth of 4 m, inserted in the sediment, and kept closed throughout the experiment. The experiment comprised three treatments: i) Natural environment (N), i.e. in the natural water outside the mesocosms containing a rope of 30 oysters (Crassostrea gigas), ii) Control mesocosm (C) filled with natural water with no oysters, and iii) Oyster mesocosm (O) filled with natural water containing a rope of 30 oysters. Oyster respiration in the oyster mesocosm depleted oxygen after 54 h. All the oysters from O mesocosm were dead after nine days and decomposition of their flesh combined with releases from the water-sediment interface increased dissolved inorganic nitrogen (dominated by ammonium), phosphates, and ∑H2S up to 390, 17 and 295 μmol·L−1, respectively. Phytoplankton biomass consequently increased by 20 (11.8 μg chlal −1) and abundance by 4.5 (186 × 106 cells·L1) dominated largely by green algae <5 μm. During the oyster mortality period (day 6 to day 9) high abundances of heterotrophic flagellates and large ciliate specimens were observed. This shift in the community towards small phytoplankton favours the microbial loop and is detrimental to shellfish farming. In a context of global warming in which the risk of anoxia is higher, the results of the present investigation demonstrate that anoxia triggers shellfish mortality and that the change in the plankton community disrupts the normal functioning of the ecosystem, causing serious financial losses. In this context, it is crucial to predict possible hypoxia and anoxia events using high frequency measurements of dissolved oxygen, by avoiding using shallow zones for oyster production and by reducing shellfish stocks, or by mechanically lifting the oysters out of the water during the night to reduce oxygen respiration in the ecosystem