The Qa-1 in mice is homologous to human leukocyte antigen E(HLA-E), and both of them belong to the non-classical major histocompatibility complex I b(MHC-I b) molecules. Qa-1 is capable of presenting self or exogenous antigen peptides to interact with two distinct receptors, namely T cell receptor (TCR) and natural killer cell group 2 member A (or C) (NKG2A/C), thus playing an important role in immune response and regulation. Qa-1-restricted regulatory CD8+ T cell (CD8+ Treg) is one of the most studied CD8+ Treg subgroups, which can maintain immune homeostasis and autoimmune tolerance by exerting immunosuppressive effects. Consequently, Qa-1-restricted CD8+Treg cells are closely associated with the occurrence and development of various clinical diseases, such as tumors, infections, autoimmune diseases, and transplant rejections. This paper provides a comprehensive review of the phenotypic characteristics, functional effects, regulatory mechanisms of Qa-1-restricted CD8+ Treg cells, as well as the latest research progresses of Qa-1-restricted CD8+ Treg cells involved in the pathogenesis of infectious diseases.