Although intramammary xanthosine (XS) treatment was reported to increase the mammary stem cell population and milk yield in bovine and caprine, underlying molecular mechanisms remain unclear.The goal of this study was to evaluate effects XS treatment on the mammary transcriptome in early lactation dairy goats. Primiparous Beetle goats were used. Five d after kidding, one gland was infused with XS (TRT) twice daily for 3 d, and the other gland served as control (CON). Milk from TRT and CON glands was collected 10 d after the last treatment, followed by RNA extraction from milk fat globules (MFGs). MFGs primarily contains transcripts of mammary epithelial cells (MEC) origin. We characterized XS-induced transcriptome changes in MECs of 2 goats, using RNA sequencing technology. Processed reads were aligned to the goat genome using STAR. Transcript raw read counts were obtained using HTseq. Differential transcript analysis was performed using cuffdiff and DESeq2. Differentially expressed genes (DEGs; q <0.002) were used to identify Gene Ontology terms (PANTHER) and gene networks (STRING db). Response to XS treatment was based on identification of DEGs between TRT and CON glands of each goat. Pathways impacted by these DEGs include cell communication, cell cycle and cell proliferation. A predominant portion of the DEGs showed downregulation by XS treatment. Functional prediction of these genes include (i) regulation of inflammatory and immune response (TLR4, IL8, CDKN1A (p21), S100A8, S100A12, VIM) and (ii) anti-proliferative signals by dual specificity phosphatases (DUSP). Remaining DEGs reflected upregulation by treatment. Predicted function of these genes include (i) mRNA processing and splicing; (ii) and signaling pathways. Notably, upregulation of RHOA highlighted its potential role in modulating response to XS through: (i) linking plasma membrane receptors, (ii) involvement of focal adhesion and (iii) regulating cellular response to stimulus. This study documents XS-induced transcriptome changes in milk producing cells of goats and suggests XS treatment is likely associated with molecular mechanisms of enhanced cell proliferation in milk producing cells in goats.