Hand‑foot syndrome (HFS) is defined as a major adverse reaction to capecitabine; however, the underlying mechanisms remain unclear. In total, 85 patients who were taking oral capecitabine were included in the present study and these patients were divided into HFS‑positive and HFS‑negative groups. Serum samples were collected from patients and an untargeted metabolomics analysis was conducted using ultra‑high performance liquid chromatography‑mass spectrometry/mass spectrometry. The present study aimed to investigate the presence of metabolites in the serum of patients that developed HFS in response to capecitabine treatment. A total of 193 differential metabolites were identified, with 134 upregulated and 59 downregulated. Bioinformatics analysis revealed four novel metabolites that may be associated with HFS. Subsequent in vitro experiments were conducted to explore the damaging effects of capecitabine and its associated metabolites on human adult keratinocyte cell line, TPA‑treated (HaCaT) cells. Results of the present study revealed that aciclovir and lamivudine affected cellular damage at the highest level. In conclusion, the present study aimed to systematically and comprehensively describe the metabolites present in patients with capecitabine‑induced HFS and may further the current understanding of the capecitabine pathways that play a key role in HFS.