Migraine is a prevalent, disabling type of primary headache disorder associated with a high socioeconomic burden. The clinical management of migraine is challenging. This study was to identify potential serum lipidomic biomarkers of migraine. The serum lipidomic profile of migraine sufferers was compared with healthy individuals using Liquid Chromatography coupled to Mass Spectrometry (LC-MS). Volcano plot analysis by Student’s t-test was performed to identify the differential metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under ROC curves (AUC) was calculated to evaluate whether the metabolites could be efficiently exploited for constructing a sensitive biomarker of migraine. A total of 29 serum metabolites from 4 classes of lipids including acylcarnitines, non-alpha-hydroxy-sphingosine ceramides (Cer_NSs), lysophosphatidylcholines (lysoPCs) and lysophosphatidylethanolamines (lysoPEs) were significantly different in migraine patients and controls. Of note, Cer_NSs were significantly elevated and lysoPEs were significantly decreased in migraine patients. LysoPE 18:1, lysoPE 18:2 and lysoPE 22:5 were found to be decreased in both positive and negative ion mode. Moreover, except for lysoPC 20:0, other lysoPCs were decreased in migraine patients. ROC curve analysis indicated that lysoPC 16:0 and lysoPC 20:0 are potential sensitive and specific biomarkers for migraine. LysoPC 16:0 and lysoPC 20:0 may be potential biomarkers for migraine. We suggest therapeutic management of these metabolites may be helpful in the prevention and treatment of migraine.