Background: Deep brain stimulation (DBS) is recommended for the treatment of advanced Parkinson’s disease (PD), though individual reactions may be different. There are currently no clinically available biomarkers for predicting the responses of PD patients to DBS before surgery. This study aimed to determine serum biomarkers to predict DBS responses in PD. Methods: We profiled differentially expressed proteins (DEPs) in serum samples and identified potential biomarkers to predict the therapeutic responses to DBS in PD patients. Ten serum samples were selected from PD patients to identify DEPs via mass spectrometry proteomics; these were then verified by enzyme-linked immunosorbent assay in another 21 serum samples of PD patients. Results: The present study identified 14 DEPs (10 downregulated and four upregulated DEPs) with significantly different levels between non-responders and responders. Most of the DEPs were related to amino acid metabolism and protein modification pathways. Bleomycin hydrolase (BLMH) and creatine kinase M-type (CKM) were found to be significantly downregulated in the responders. Additionally, subsequent logistic regression and receiver operating characteristic analyses were performed to determine the diagnostic performance of candidate proteins. Conclusions: The identified DEPs show potential as biomarkers for the accurate evaluation of DBS therapeutic responses before surgery. Furthermore, assessment of serum BLMH and CKM may be particularly useful for predicting the therapeutic responses to DBS in PD patients.