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The Mediterranean Sea is considered a hot spot of global warming because it has been changing faster than the global ocean, creating a strong impact on the marine environment. Recent studies agree on the increase in the sea level, in the sea surface temperature, and in the sea surface salinity in the Mediterranean Sea over the last two decades. In this research, the possible interconnection between these and other parameters that contribute to the regulatory effect of the sea on the climate are identified and discussed. Spatio-temporal variability of four oceanographic and air–sea interaction parameters (sea-level, sea surface temperature, sea surface salinity, and freshwater flux) are estimated over the last 27 years by performing the empirical orthogonal function analysis. Climatic trends, and interannual and decadal variability of the different datasets are delineated and described in the whole Mediterranean and in its sub-basins. On the climatic scale, the Mediterranean and its sub-basins behave in a coherent way, showing the seal level, temperature, salinity, and freshwater flux rise. On the interannual scale, the temporal evolution of the sea level and sea surface temperature are highly correlated, whereas freshwater flux affects the variability of sea level, temperature, and the salinity field mainly in the Western and Central Mediterranean. The decadal signal associated with the Northern Ionian Gyre circulation reversals is clearly identified in three of the four parameters considered, with different intensities and geographical extents. This signal also affects the intermediate layer of the Eastern Mediterranean, from where it is advected to the other sub-basins. Decadal signal not associated with the Northern Ionian Gyre reversals is strongly related to the variability of main sub-basin scale local structures.