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Background Trichomoniasis is the most common non-viral sexually transmitted disease caused by the protozoan parasite Trichomonas vaginalis. Metronidazole (MTZ) is a widely used drug for the treatment of trichomoniasis; however, increased resistance of the parasite to MTZ has emerged as a highly problematic public health issue. Methods We conducted iTRAQ-based analysis to profile the proteomes of MTZ-sensitive (MTZ-S) and MTZ-resistant (MTZ-R) parasites. STRING and gene set enrichment analysis (GESA) were utilized to explore the protein-protein interaction networks and enriched pathways of the differentially expressed proteins, respectively. Proteins potentially related to MTZ resistance were selected for functional validation. Results A total of 3123 proteins were identified from the MTZ-S and MTZ-R proteomes in response to drug treatment. Among the identified proteins, 304 proteins were differentially expressed in the MTZ-R proteome, including 228 upregulated and 76 downregulated proteins. GSEA showed that the amino acid-related metabolism, including arginine, proline, alanine, aspartate, and glutamate are the most upregulated pathways in the MTZ-R proteome, whereas oxidative phosphorylation is the most downregulated pathway. Ten proteins categorized into the gene set of oxidative phosphorylation were ATP synthase subunit-related proteins. Drug resistance was further examined in MTZ-S parasites pretreated with the ATP synthase inhibitors oligomycin and bafilomycin A1, showing enhanced MTZ resistance and potential roles of ATP synthase in drug susceptibility. Conclusions We provide novel insights into previously unidentified proteins associated with MTZ resistance, paving the way for future development of new drugs against MTZ-refractory trichomoniasis.

Additional file 4: Table S3. Differentially expressed proteins involved in the hydrogenosomal energy metabolism in the MTZ-R proteome.

Additional file 1: Table S1. Primers used in this study.

Additional file 6: Table S5. Enriched downregulated KEGG pathways in the MTZ-R proteome in response to MTZ treatment.

Additional file 5: Table S4. Enriched upregulated KEGG pathways in the MTZ-R proteome in response to MTZ treatment.

Additional file 8: Table S7. Enriched downregulated GO functional annotations in the MTZ-R proteome in response to MTZ treatment.

Additional file 7: Table S6. Enriched upregulated GO functional annotations in the MTZ-R proteome in response to MTZ treatment.