The Marano and Grado Lagoon (Adriatic Sea, Italy) is an important transitional environment that furnishes numerous ecosystem services and is under protection as Site of Community Importance. It suffers from an excess of nutrients, especially nitrate (NO3−), and has been designated as a nitrate vulnerable zone. In this work, sixteen water bodies were seasonally monitored for physicochemical parameters and nutrients, to elucidate the trophic state of the lagoon and to check the occurrence of significant temporal trends in a time series from 2011 to 2021. Steep gradients of spatial and seasonal distribution were observed for all parameters with elevated concentration of N-NO3− (up to 360 µM) in the western sector. The whole lagoon was in phosphorous limitation (P-PO43− mean ± s.d. = 0.15 ± 0.22 µM) with a mean Redfield ratio of 1130. The concentration of nutrients was significantly correlated with the degree of both freshwater inputs and precipitation. The calculation of trophic indices shows that the lagoon is in an oligotrophic to hypertrophic condition (i.e., TRIX 1.9–6.8). The analysis of the temporal series showed that despite some significant trends, the time span considered is too short to detect significant changes in the trophic state of this dynamic environment.