Abstract Background: Ovariectomized menopausal rat model was used to investigate the effects of menopause on the sublingual salivary gland (SSG) and the potential therapeutic effect of human umbilical cord blood mesenchymal stem cells (hUCB-MSCs). Methods: Thirty rats were equally divided into three groups: sham-operated (SHAM), ovariectomized (OVX), and ovariectomized stem cells injected (OVX+ hUCB-MSCs). Expressions of α-SMA, AQP1, Sca-1, PCNA, ssDNA, and caspase-3 were determined. Homing of hUCB-MSCs was detected by fluorescence microscopy and examination of immunostained sections for human CD105 and CD34 was performed. Morphometric data were statistically analyzed using the Kruskal–Wallis test followed by Scheffé’s method. Correlation of AQP1 with Sca-1-positive sublingual stem cells was also analyzed. Results: In the SSGs of the OVX group, ballooned mucus acinar cells, atrophied serous cells, and a decreased number and height of duct lining cells were observed. The interstitial spaces were edematous, and the blood vessels were congested. The significant decrease in the positive area % of α-SMA and AQP1, the number of Sca-1-positive sublingual stem cells, and proliferating cells was associated with a significant increase in apoptotic cells. The OVX+hUCB-MSCs group showed significant structural improvement, manifested by the normal appearance of mucus and serous acini, as well as the number and height of striated duct cells. A significant increase in the positive area % of α-SMA and AQP1 and the number of proliferating and Sca-1-positive sublingual stem cells was observed. Interestingly, a significantly positive Pearson’s correlation between the area % of AQP1 and the number of Sca-1-positive sublingual stem cells was also recorded. Conclusion: Our results indicated a positive effect of hUCB-MSCs therapy for SSG pathology in a post ovariectomy rat model as evidenced by an improvement in the histologic architecture, upregulation of the immunostained area % of α-SMA and AQP1, increase in the number of Sca-1-positive sublingual stem cells and proliferating cells, and down regulation of apoptotic cells.