Metabolic profiling employing hydrogen nuclear magnetic resonance (¹H NMR) spectroscopy and chemometric analysis of human blood serum samples taken from the control group (n = 25) and patients with bipolar disorder (n = 25) was performed to identify molecular changes related to the disorder and to different drug treatments: lithium (n = 15) versus other medications (n = 10). This strategy showed significant potential for exploring pathophysiological and toxicological features involved in bipolar disorder. The investigated groups (control and patients with bipolar disorder under different treatments) could be distinguished according to their metabolic profiles, and the main differential metabolites found were lipids, lipid-metabolism-related molecules (acetate, choline, and myo-inositol), and some key amino acids (glutamate, glutamine). Our results suggest that some of the 24 identified metabolites may be linked to lithium- and other-medication-provoked metabolic changes or may even be directly related to the disorder. Thus, these findings may contribute to paving the way for future studies aiming at identifying potential biomarkers for bipolar disorder.