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Objective: To screen new serum metabolic biomarkers for different drug resistance profiles of pulmonary tuberculosis (TB) and explore their mechanisms and functions., Methods: We collected serum samples from TB patients with drug sensitivity (DS), monoresistance to isoniazid (MR-INH), monoresistance to rifampin (MR-RFP), multidrug resistance (MDR), and polyresistance (PR). The metabolites in the serum samples were extracted by oscillatory and deproteinization for LC-MS/MS analysis, and the results were normalized by Pareto-scaling method and analyzed using Metaboanalyst 4.0 software to identify the differential metabolites. The differential metabolites were characterized by function enrichment and co-expression analysis to explore their function and possible pathological mechanisms., Results: Compared with the DS group, 286 abnormally expressed metabolites were identified in MR-INH group, 362 in MR-RPF group, 277 in MDR group and 1208 in PR group by LC-MS/MS analysis. Acetylagmatine ( P < 0.05), aminopentol ( P < 0.05), and tetracosanyl oleate ( P < 0.05) in MR-INH group; Ala His Pro Thr ( P < 0.001) and glycinoprenol-9 ( P < 0.05) in MR-RFP group; trimethylamine ( P < 0.05), penaresidin A ( P < 0.05), and verazine ( P < 0.05) in MDR group; and PIP (18:1(11Z)/ 18:3(6Z, 9Z, 12Z)) ( P < 0.001), Pro Arg Trp Tyr ( P < 0.001), N-methyldioctylamine ( P < 0.001), and phytolaccoside E ( P < 0.05) in PR group all showed significant differential expressions. Significant differential expressions of phthalic acid mono-2-ethylhexyl ester ( P < 0.05) and eicosanoyl-EA ( P < 0.05) were found in all the drug resistant groups as compared with DS group., Conclusions: Acetylagmatine, aminopentol, tetracosanyl oleate, Ala His Pro Thr, glycinoprenol-9, trimethylamine, penaresidin A, verazine, PIP(18:1(11Z)/18:3(6Z, 9Z, 12Z)), Pro Arg Trp Tyr, N-methyldioctylamine, phytolaccoside E, phthalic acid mono-2-ethylhexyl ester, and eicosanoyl-EA are potentially new biomarkers that indicate monoresistance, multi-drug resistance and polyresistance of Mycobacterium tuberculosis. The combined use of these biomarkers potentially allows for assessment of drug resistance in TB and enhances the diagnostic sensitivity and specificity.