Objective To evaluate the correlation between the changes of vascular density in deep and shallow layers， retinal hyperreflexia and the therapeutic response of diabetic macular edema （DME）. Methods Retrospectively selected DME patients （45 cases and 59 eyes） who visited the Department of Ophthalmology from April 2020 to November 2023 as the experimental group. Compare the change of deep and superficial blood vessel density and retinal hyperreflective points before and after treatment of the patients. The correlation between each index and poor response to anti-vascular endothelial growth factor （VEGF） treatment with DME was analyzed using the Pearson test. The value of baseline deep retinal capillary plexus （DCP）， central macular retinal thickness （CMT）， number of high-reflective foci （HRF） in the retina， and blood flow density （FD300-VD） in diagnosing poor response to anti-VEGF therapy in DME was analyzed using the subject operating characteristic curve （ROC）. Results Compared with pre-treatment， patients' superficial retinal capillary plexus （SCP）， DCP， FD300-VD， and deep-superficial flow ratio （DSFR） increased and CMT thickness significantly decreased after treatment （P < 0.05）. Pearson's correlation test showed that the outcome of patients with poor response to anti-VEGF therapy was negatively correlated with baseline SCP-VD， DCP-VD， DSFR， and FD300-VD （r = -0.458， -0.433， -0.604， and -0.452， P < 0.05） and positively correlated with CMT （r = 0.427， P < 0.05）. The results of multifactorial logistic regression analysis showed that a rise in SCP， DCP， FD300-VD， and DSFR， and a decrease in CMT were correlates affecting the response to anti-VEGF therapy in DME （OR = 0.285， 0.272， 0.291， 0.268， 2.821， P < 0.05）.The results of ROC curve analysis showed that the AUCs of baseline DCP， CMT， HRF quantity， and FD300-VD were 0.918， 0.934， 0.947， and 0.927， respectively， which were of good value in diagnosing poor response to anti-VEGF therapy in DME. Conclusion Morphologic indicators such as changes in the density of deep and superficial blood vessels and retinal hyperreflective spots have good application value in assessing the response to DME treatment and can assist in clinical treatment.