Background: The aim is to probe into the differential expression of miRNA in macrophage exosomes in diabetic nephropathy (DN) by ERK regulating macrophage polarization through the NF-kappa B/JAK-STAT signaling pathway. Methods: Our team cultivated the mouse macrophage line RAW264 cells. When the cell growth status was good, we added 30 mmol/L glucose, and then added ERK/JAK-STAT/NF-kappa B inhibitors separately. We adopted western blot for observing macrophage polarization and the impact of JAK-STAT inhibitor on caspase-9, eNOS, NF-kappa B p65 expression, extracted exosomes, and total exosome RNA of each group of cells. Their miRNA expression profiles were also analyzed by high-throughput sequencing. Results: (1) In comparison with the control group, relative iNOS protein expression in ERK inhibitor group dramatically declined (p < 0.05), and the iNOS protein content in the NF-kappa B inhibitor group and the JAK-STAT inhibitor group conspicuously dwindled (p < 0.05); relative CD206 protein expression in each inhibitor group was clearly augmented (p > 0.05). Under the intervention of high glucose, ERK/JAK-STAT/NF-kappa B inhibitors brilliantly diminished the up-regulation of caspase-9 (p < 0.05), and ERK/JAK-STAT inhibitors notably minimized the up-regulation of NF-kappa B p65 (p < 0.05). ELISA results unveiled that in contrast to the control group, TNF-alpha, IL-1 beta, and CXCL10 levels in the macrophage supernatant of the inhibitor group was tellingly augmented (p < 0.05), whereas TGF-beta level had strikingly declined (p < 0.05), proving that macrophages were activated to M1. (2) Flow cytometry uncloaked that the phagocytic ability of macrophages in inhibitor group was compellingly lower than that in the control group. (3) One hundred thirty-six known miRNAs with notably differential expression and 5,134 miRNA sequences were detected in the exosomes of the macrophage supernatant of each experimental group. Of those, some differentially expressed miRNAs include miR-193a-3p, miR-1260B, and miR-3175. miR193a-3p, miR-1260B, and miR-3175 extensively participate in the development of cancer, arthritis, osteogenic differentiation, Alzheimer's disease, and other diseases, as well as in the regulation of MAPK/ERK, TLR4/NF-kappa B, and other signaling pathways. Conclusions: ERK modulates macrophage activation to M1 and alters exosome miRNA expression profile via NF.B/JAK-STAT pathway.