Well-differentiated/dedifferentiated liposarcomas (WD/DDLPSs) account for ∼60% of all liposarcomas. They have a poor prognosis due to limited therapeutic options. WD/DDLPSs are characterized by aberrant expression of mouse double minute 2 (MDM2), which forms G-quadruplexes (G4s) in its promoter. Here, we investigated the possibility of targeting WD/DDLPSs with small molecules against the MDM2 G4s. Among the molecules tested, the naphthalene diimide derivative QN-302 significantly impaired WD/DDLPS cell growth and its activity strikingly paralleled cell-specific G4 abundance as measured by CUT&Tag and RNA sequencing analysis. QN-302 stabilized MDM2 G4s at the P2 inducible promoter and prevented polymerase progression from the constitutive P1 promoter, thereby inhibiting the formation of full-length MDM2 transcripts. This resulted in the accumulation of p53 through the p53-MDM2 autoregulatory feedback loop, ultimately leading to apoptotic cell death. In patient-derived xenograft mouse models, QN-302 treatment reduced tumour volume distribution and was well tolerated. We have identified a novel and effective therapeutic strategy to reduce MDM2 expression and promote p53 reactivation in tumours harbouring wild-type TP53, such as WD/DDLPSs.