This study elucidates the physicochemical mechanisms of monovalent and multivalent inorganic scaling and suggests an optimal cleaning strategy for efficient membrane distillation (MD) operation. Three distinct stages of MD inorganic scaling were clearly identified by i) experimentally measuring transient flux, ii) rejection behavior resulted from the deposition of a scale, and iii) SEM-EDX analysis of the membrane. During stage 1, no scale was found over the membrane surface showing almost stable water flux and permeate conductivity. In stage 2, the onset of inorganic scaling resulted in the deposition of scaling on some parts of the membrane surface, partially covering the membrane pores, which lead to a sudden reduction in the water flux despite a steady solute rejection. However, as scaling expands into the pore in final stage 3, the permeate conductivity increased, indicating a reduction in rejection. Then, the pores were completely blocked, and the water flux reached almost zero. To simulate this scaling formation more fundamentally, the saturation index (SI) and supersaturation (S) concepts were introduced. The type and timing of scaling were successfully predicted by the SI value, and the amount of scaling was accurately estimated by the S value. Moreover, through the analysis of this physicochemical mechanism of inorganic scaling, an optimal cleaning strategy for sustainable MD operation was proposed.