The formation of mutant p53 aggregates is caused by the exposure of the adhesion sequences wrapped in the hydrophobic core of p53 after mutation. After exposure, the adhesion sequences will quickly nucleate and assemble to form amorphous fibrils. The mutant p53 aggregates can not only inactivate wild type p53 (Wt-p53) in a dominant-negative effect manner, but also exhibit gain-of-function (GOF) characteristic to promote the development and progression of tumors. Abnormal aggregation of mutant p53 has been found in various tumors, such as ovarian cancer, colon cancer and prostate cancer. The mutant p53 aggregates are significantly correlated with tumor metastasis, drug resistance and poor prognosis. Therefore, p53 aggregation is considered as a potential therapeutic target. The discovery of small molecule compounds targeting mutated p53 aggregates, which can inhibit the exposure of adhesion sequences in the hydrophobic core of p53 and restores the function of p53, is becoming a promising strategy in cancer therapy. In this review, we summarized the mechanism of p53 aggregation and the potential therapeutic strategies.