Abstract: Background: Embryo mortality during early gestation limits litter size in swine. Sodium butyrate (SB) is a potential feed additive for improving gut health and productivity. Objective: To evaluate the effects of SB supplementation during early gestation on reproductive performance in sows and mice. Methods: In the sow trial, gestating sows were fed diets supplemented with 0% (Ctrl), 0.05% (LSB), 0.10% (MSB), or 0.20% (HSB) SB from gestation day (GD) 1 to 28. Fecal samples (GD14 and GD28) underwent 16S rRNA sequencing and metabolomics. Litter performance was recorded at farrowing. In the mouse trial, identical SB doses were given from GD1 to GD6. Implantation sites were counted on GD6, and uterine tissues were subjected to transcriptomics and proteomics. Colonic content and serum were analyzed by 16S rRNA sequencing and metabolomics. Results: In sows, the LSB group exhibited significant increases in total litter size, live litter size, and healthy litter size compared to the Ctrl group. Similarly, in mice, SB supplementation significantly increased the number of embryo implantation sites. Integrated multi-omics in mice revealed that SB reshaped the gut microbiota (enriching Lactobacillus and Bifidobacterium) and colonic metabolome, upregulating uterine endometrial receptivity-related genes (Wnt4 and H19). Conclusions: SB supplementation is associated with alterations in the gut microbiota, serum metabolome, and uterine transcriptome/proteome, suggesting a potential link between these compartments that may contribute to improved embryo implantation. SB represents a promising nutritional strategy to improve reproductive efficiency in swine and potentially other mammals.