Background As a group of membrane-anchored proteins, the proteins containing a disintegrin and metalloprotease domain (ADAMs) control many biological processes, especially for male fertility. Mouse Adam21 was previously found to be specifically expressed in the somatic cells and germ cells of testes, but its functional role during spermatogenesis and male reproductive processes is still unknown. Methods Adam21-null mice were created using the CRISPR/Cas9 system. Quantitative real-time PCR was used for analyzing of gene expression. Histological, cytological and immunofluorescence staining were performed to analyze the phenotypes of mouse testis and epididymis. Intracellular lipid droplets (LDs) were detected by Oil red O (ORO) staining and BODIPY staining. Fertility and sperm characteristics were also detected. Results Here, we successfully generated an Adam21 conventional knockout mouse model via CRISPR/Cas9 technology so that we can explore its potential role in male reproduction. We found that male mice lacking Adam21 have normal fertility without any detectable defects in spermatogenesis or sperm motility. Histological analysis of the seminiferous epithelium showed no obvious spermatogenesis difference between Adam21-null and wild-type mice. Cytological analysis revealed no detectable defects in meiotic progression, neither Sertoli cells nor Leydig cells displayed any defect compared with that of the control mice. All these results suggest that Adam21 might not be essential for male fertility in mice, and its potential function still needs further investigation.