DNA repair is essential for the successful proliferation of genetic material and for transcriptional fidelity. Excision repair cross-complementation group 1 (Ercc1) is a structure-specific nucleic acid endonuclease that repairs DNA damage by participating in the nucleotide excision repair and DNA double-strand break repair pathways. The accumulation of various molecular and cellular damages over time would account for ageing. Defects in Ercc1 lead to malfunctions in DNA damage repair, resulting in the accumulation of cellular damages and ultimately inducing the occurrence of aging. This review summarized the biological functions of Ercc1 during DNA damage and the Ercc1-deficient mouse models, and discussed the biological effects of Ercc1 in different tissues associated with senescence and age-related degenerative diseases. The present review would provide potential intervention targets and theoretical basis for the development of innovative therapeutics, animal models, and drug discovery for senescence-associated diseases.