The p110δ isoform of the PI3K catalytic subunit (encoded by the PIK3CD gene) is a key component of the PI3K pathway for follicle growth in mammalian ovarian granulosa cells. Nevertheless, little is known about the association of its polymorphisms with ovine litter size. In this study, the distribution of different genotypes of two SNPs in the PIK3CD gene was calculated in more than forty sheep breeds, and the associations between SNPs and litter size in Small Tail Han (STH) sheep were also analyzed. Besides, the mRNA expression of the PIK3CD gene was also detected in some reproduction-related tissues. The results showed that the "A" allele frequency was higher in rs412889931 (g.41926327G > A) in a typical polytocous sheep breed (p < 0.01). The association's analysis showed rs412889931 was correlated with ovine fecundity as assessed by three parity litter sizes (p < 0.05). Finally, we found the expression of PIK3CD in the ovary had significant differences in different fecundity sheep breeds, indicating that SNP may regulate the litter size by influencing the PIK3CD gene expression. The present results demonstrated that rs412889931 could be used in the marker-assisted selection of the litter size in sheep breeding.