Compared to the secondary brain injury after intracerebral haemorrhage (ICH), fewer reports focused on the mechanism of primary brain injury induced by mass effect. Here, the tandem mass tag (TMT) labeling proteomics method was used to study the mechanical damage of the mass effect after ICH. A total of 5390 proteins were identified, and 4593 proteins were quantified, included 80 up-regulated proteins (M/N Ratio > 1.2) and 30 down-regulated proteins (M/N Ratio > 1.2). Bioinformatics and enrichment analysis showed that the differentially expressed proteins were mainly involved in immune response, signal transmission, and oxidative phosphorylation. The mass effect affects the synthesis and metabolism of ATP by mechanically stretching and squeezing the brain tissue. Furthermore, the cell morphology and dendritic development of neurons were also significantly influenced by mass effect, which also cause neuronal damage through the formation of oxidative stress and oxygen-glucose deprivation, and activate the neuronal protection and defense mechanisms. Our results provide the relevant channels and key proteins of primary brain injury caused by mass effect after ICH, which offer a scientific basis for the understanding of ICH injury.