Sludge conditioning is important for improved dewatering, with the sludge characteristics impacting the effect of conditioning. A composite conditioner, Fe2+ activated sodium persulfate (Fe2+/SPS) combined with phosphogypsum (PG), was used to examine its impact on sludges with different organic content or different solid content. Response surface optimization analysis shows that when the best conditioning is achieved, the reduction of the specific resistance to filtration is not sensitive to organic matter content, but the dewatering performance of the sludge is greatly affected by the solid content. The oxidation role of Fe2+/SPS and the skeleton builder role of PG, together, affect the conditioning, with oxidation playing a major role in conditioning, especially for greater organic matter content. The organic content also affects the effectiveness of the skeleton builder more than the solid content. Changes in PG significantly impacts the optimal molar ratio and dosage of Fe2+/SPS. Sludge with greater solid content requires greater Fe2+/SPS dosage to provide stronger oxidation to destroy flocs. The composite conditioning decreases the content of extracellular polymeric substances and proteins/polysaccharides with the decrease in protein content being significantly greater than that of polysaccharides, these decreases improve the sludge dewaterability.