Abstract: The calcined water treatment plant sludge powder (CWTS) was used to replace part of the cement to prepare high-volume sludge concrete, and the effect of the high-volume CWTS on the mechanical properties and microstructure of concrete was studied. The results show that although the high-volume CWTS is detrimental to the development of the 28-days compressive strength of concrete, 20wt% and 40wt% of the CWTS can significantly improve the 90-days compressive strength of concrete. The CWTS has pozzolanic reactivity and filling effect, which makes the 90-days pore structure of concrete mixed with 20wt%‒40wt%CWTS significantly refined, and the harmful pore volume (>1 µm) is significantly reduced. Meanwhile, it is observed from the nanoscale characteristics that adding 20wt%CWTS can significantly reduce the content of pore phase and unhydrated phase in the matrix, and increase the volume fraction of C—S—H phase, especially the high-density C—S—H phase. In addition, the addition of 20wt%CWTS can reduce the width of the interface transition zone (ITZ) by 20%, the addition of 40wt%CWTS and the control group (0wt%CWTS) have similar ITZ width. Therefore, using a large amount (20wt%‒40wt%) of CWTS to replace cement to prepare concrete not only has better economic and environmental benefits, but also benefits the improvement of its 90-days mechanical properties and microstructure.