Background and Purpose: Methamphetamine (METH) is an artificial synthetic non-catecholamine sympathomimetic central stimulant that has been widely abused in recent years, and the abusers are at increased risk of various infectious diseases owing to immune system disorders. Dopamine D1 receptor (DRD1) is a key receptor in the mechanism research of drug addiction and a crucial molecule bridging the nervous and immune systems. Experimental Approach: To understand the peripheral immunomodulatory effect of METH, and the role of DRD1 in this process, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from METH-treated wild-type or DRD1 knockout mice, and controls. Key Results: We report the first specific evidence of the immunosuppressive effects of chronic METH exposure on PBMCs by subset proportion, cell proliferation, cell interaction, gene expression and functional signalling with partial involvement of DRD1. METH shifted a specific B cell subcluster from Ifi27l2a+B to Hba-a2+B, a CD4T cell subcluster from Ifit1+CD4T to Sepp1+CD4T, and a CD8T cell subcluster from Dapl1+CD8T to Lef1+CD8T. Furthermore, scRNA-seq revealed the possible mechanism of DRD1 involvement in METH regulation of immune responses. Conclusion and Implications: The results from the study are expected to be a diagnostic and therapeutic standard of METH abused, and a new therapeutic strategy based on DRD1.