Excess levels of Magnesium (Mg) in irrigation waters and/or in soils in combination or alone with sodium (Na) may result in soil degradation through impacts on soil physical properties. In some regions of Central Asia such as southern Kazakhstan, water used for irrigation contains Mg2+ levels higher than Calcium (Ca). More than 30% of irrigated area in Kazakhstan is represented by Mg-dominated soils, which exhibit low infiltration rates and hydraulic conductivities. The consequence has been a gradual decline in yield of cotton (Gossypium hirsutum L.), which is commonly grown in the region. These soils need an adequate quantities of Ca to replace excess Mg from the cation exchange sites with a subsequent decrease in Exchangeable Magnesium Percentage (EMP). As a source of Ca, phosphogypsum is available in some parts of Central Asia as an industrial waste and needs appropriate disposal. In participation with the local farming communities, we carried out a 4-year field experiment in southern Kazakhstan to determine the effects of different soil application rates of phosphogypsum (0, 4.5, and 8.0 t/ha) on chemical changes in a Mg-dominated soil, cotton yield, and economics. Water used from the Arys Turkestan for irrigation had Mg to Ca ratio in the range of 1.30 to 1.66. The application of phosphogypsum increased Ca concentration in soil solution and triggered the replacement of excess Mg from the cation exchange sites. After harvest of the first cotton crop, there was 18% decrease in EMP of the surface 0.2 m soil over the pre-experiment level in the plots where phosphogypsum was applied at 4.5 t/ha. Other phosphogypsum application at 8 t/ha caused 31% decrease in EMP at the same soil depth. Another beneficial effect of phosphogypsum application was an increase in phosphorus content of the soil. The 4-year average cotton yields were: phosphogypsum at 8 t/ha (cotton yield = 2.6 t/ha), phosphogypsum at 4.5 t ha–1 (cotton yield = 2.4 t/ha), and control (cotton yield = 1.4 t/ha). Since the amendment was applied once at the beginning of the experiment, exchangeable Mg levels tended to increase after 4 years of its application, particularly in the 4.5 t/ha treatment. Thus there would be a need for another application of the amendment to such soils after every 4 years to optimize ionic balance and to sustain higher levels of cotton production.