In this study, the effect of microbiological preparations on the microbiological and agrochemical properties of highly saline soil (0–30 cm) during cotton cultivation was investigated. The use of preparations contributed to an increase in the number of all studied physiological groups of microorganisms. The number of ammonifiers, fungus and cellulose-decomposing microorganisms increased by 1 order of magnitude, and humus-decomposing microorganisms by 2 orders of magnitude. The appearance of phosphorus-mobilizing bacteria, previously absent in the original soil, was noted. Positive changes in the agrochemical composition of the soil were also revealed: the content of mobile phosphorus increased by 3.8 mg/kg, and the amount of mobile potassium decreased by 102.6 mg/kg. A decrease in soil pH from 7.95 to 7.45 and a decrease in total salinity from 1.72 to 0.09% were noted, which indicates improved conditions for plant growth and the activity of soil microorganisms. The obtained results confirm the effectiveness of using microbiological preparations in increasing the biological activity and fertility of saline soils.