Objective To investigate the effect of low-molecular-weight heparin on the EGFR/ PI3K/ Akt signaling pathway, to explore its effect on endometrial angiogenesis during blastocyst implantation, and to evaluate the mechanism of the drug’s effect on endometrial receptivity. Methods Seventy-two C57BL/ 6 mice were randomly divided into six groups: blank group, model group, aspirin group, low-molecular-weight heparin high-dose group, low-molecular-weight heparin medium-dose group, and low-molecular-weight heparin low-dose group. Apart from the blank group, in the remaining groups indomethacin was used to establish a blastocyst implantation disorder model. On the morning of the fifth day of pregnancy, the mice were sacrificed by cervical dislocation and the number of uterus-implanted blastocysts was counted. The expression of HBEGF, EGFR, PI3K, and Akt in endometrium was determined by immunohistochemistry, Western Blotting, and Real-time PCR. Results Compared with the model group, the mice in the blank group and the drug treatment group had uteruses with ruddy, uniformly distributed implants, and a greater number of implanted sites ( P< 0. 05). The endometrial HE-stained epithelial cells were thick, the interstitial cells were large and compactly arranged, and there were more glands and blood vessels. The protein and mRNA expression levels of HBEGF, EGFR, PI3K, and Akt in the endometrium with low molecular weight heparin and high dose was higher than that of each group ( P < 0. 05). Conclusions Low-molecular-weight heparin can promote the expression of HBEGF and activate the EGFR/ PI3K/ Akt signaling pathway, thereby improving endometrial receptivity and increasing the success rate of blastocyst implantation.