The study presents the results of the first multiannual oceanographic monitoring in the coastal area of Karadag Nature Reserve and adjacent water areas in May and September in the period from 2004 to 2021. Significant and unprecedentedly high increasing trends were detected for salinity in May. Increasing trends in nitrate concentration in Koktebel Bay were noted both for May and for September. The five-day biochemical oxygen demand (BOD5), ammonium and phosphate concentrations demonstrated mostly negative trends for the measurements in May and positive trends in September. Significant decreasing trends in phytoplankton biomass were noted in September, which fit in the range of the larger-scale phytoplankton trends reported in the literature. The position of the extrema of nutrients in the long-term-average and trend slope maps was confined to the areas of increased hydrodynamic and anthropogenic activity. Multivariate analysis showed significant negative correlations of the quantitative phytoplankton characteristics with salinity, which were explained by the effect of the freshened and nutrient-enriched Azov plume. The absence of significant correlations with nutrients was attributed to the non-conservative and stochastic character of the nutrient inflow on the yearly scale and time lag between the nutrient supply and the phytoplankton growth. The large percentage of occurrences of low BOD5 values at any station indicates the unpolluted status of the area under research, which is confirmed by the low trophic index values and appearance of probability distributions of the nutrient concentrations.