Objective Comprehensive assessment of serum lipidomic alterations by glucagon-like peptide-1 receptor agonist (GLP-1 RA) has not been conducted. An approach using targeted lipidomics was applied to determine whether lipid profiles are altered in type 2 diabetes (T2D) management in response to GLP-1 RA therapy. Methods Twelve newly diagnosed T2D patients and six healthy controls were enrolled in this study and serum lipid profiles were compared using liquid chromatography-mass spectrometry prior to and following dulaglutide and liraglutide treatments. Results T2D patients include 6 that received dulaglutide and 6 that received liraglutide treatment. Compared to the healthy controls, a total of 9 species involving 53 lipids were identified that exhibited a significant (p < 0.05) differential abundance in T2D patients. The lipidomic signature of T2D before treatment was characterized by an elevated level of the diglyceride (DG) cluster that was consistently positively correlated with fasting blood glucose, body mass index, and insulin resistance index while negatively correlated with islet beta cell function. Lyso-phosphatidylcholine (LPC) 18:0 and LPC (35:4) displayed strong negative associations with glycosylated hemoglobin and body mass index. Dulaglutide treatment significantly (p < 0.05) improved serum levels of 7 lipids including DG, fatty acids, and lyso-phosphatidylethanolamine (LPE), while 10 DG, phosphatidylcholine, LPC, and SM lipid members were significantly decreased after liraglutide treatment. Differentially abundant lipids in both groups were not accompanied by an improvement in total cholesterol, low-density lipoprotein cholesterol, or high-density lipoprotein cholesterol levels. Conclusion Our study confirmed that early-stage T2D patients display broad lipidomic abnormalities that could be at least partially improved after GLP-1 RA treatment.