Climate change is one of the main problems currently strongly conditioning ecosystems all over the world. Coastal lagoons are amongst the most vulnerable habitats, and they are undergoing extensive human impact due to their high production rates and the close proximity of urban and agricultural centers. The Mar Menor, the largest saltwater lagoon in Europe, is an example of a highly impacted ecosystem. In December 2016 and September 2019, climate change-induced DANA (upper-level isolated atmospheric depression) flooding events took place there, temporarily altering the lagoon oceanographic properties. Data gathered throughout the lagoon (11 stations inside and 1 outside the lagoon) from 2016 to 2021 were analyzed in order to assess the variability of seawater parameters: salinity, density, chlorophyll-a, turbidity, and dissolved oxygen, due to DANA events. Results showed a change in seawater parameters that were reestablished at different rates, 4 and 10 months in 2016 and 2019, respectively, following a description of the environmental conditions and effects that have been reported after extreme rainfall in the lagoon. The amount of rainfall correlated with changes in the analyzed seawater parameters, such as an increase in turbidity and chlorophyll-a values. Furthermore, turbidity correlated with chlorophyll-a and oxygen saturation, while density correlated with salinity. Such extreme weather events are worsened by climate change, growing more frequent and between shorter intervals in time. In order to decelerate ecosystem decline, comprehensive management plans are needed to address the various factors that might add to anthropic impacts in natural environments.