ABSTRACTMidnolin (MIDN) is a protein coding gene that promotes the destruction of transcription factors encoded by immediate‐early genes. Previous research has found that those immediate‐early genes are involved in tumour progression. However, the role of MIDN is still not clearly identified in human cancers. With the help of the TCGA, GTEx, and HPA databases, we revealed that the expression of MIDN was disordered in cancers. MIDN is a potential prognostic biomarker in liver cancer and bladder cancer. Prognostic analysis indicates that the expression level of MIDN gains survival benefits or promotes progression in multiple tumours. After analysing the sequencing results of TCGA via Gene Set Enrichment Analysis (GSEA), results suggested the regulative role of MIDN in cell proliferation and tumour immunity. Single cell sequencing results revealed that MIDN is highly expressed in several tumour tissues and also expressed in immune cells. With the help of the ESTIMATE, TIMER, and CIBERSORT databases, we analysed the immune score, immune cell infiltration, and anti‐cancer immunity cycle depending on the expression of MIDN. Results showed that low MIDN levels are tightly associated with high CD4 + T and NK cell infiltration. Furthermore, mutations of MIDN in cancers were significantly associated with immune cell infiltration. This study presents a robust link between the expression of MIDN and tumour progression across multiple cancer types. The MIDN/CTNNB1/MMP9 axis promotes liver cancer progression via inducing a suppressive tumour immune microenvironment.