Purpose <p>This study aims to evaluate the efficacy of compression therapy in preventing oxaliplatin-induced peripheral neuropathy (OIPN) in colorectal cancer patients.</p> Methods <p>Colorectal cancer patients scheduled for their first oxaliplatin-based chemotherapy were randomly assigned to a compression therapy group or a control group. The control group received standard care, while the compression therapy group wore grade II (23–32 mmHg) compression sleeves and socks from 30 min before to 30 min after oxaliplatin infusion. Sensory and motor neuropathy incidence and symptom burden were assessed using physician evaluations and patient self-reports. Adverse events during the treatment period were also recorded.</p> Results <p>After four cycles, the compression therapy group had a significantly lower incidence of grade ≥ 2 sensory and motor neuropathy compared to the control group (sensory: 41.4% vs. 80.6%, <i>P</i> = 0.002; motor: 34.5% vs. 67.7%, <i>P</i> = 0.010). EORTC QLQ-CIPN20 scores were also significantly lower in the compression therapy group after the third and fourth cycles (<i>P</i> &lt; 0.05). Longitudinal analysis using a mixed-effects model showed a statistically significant difference in the trend of increasing OIPN incidence between the two groups (sensory: <i>OR</i> = 0.294, <i>P</i> = 0.001; motor: <i>OR</i> = 0.265, <i>P</i> = 0.001). Additionally, the compression therapy group had significantly lower EORTC QLQ-CIPN20 scores (<i>β</i> = − 2.157, 95% CI = [− 3.050, − 1.264], <i>P</i> &lt; 0.001). No adverse events related to compression therapy were observed.</p> Conclusion <p>Compression therapy reduces the incidence and severity of oxaliplatin-induced peripheral neuropathy in colorectal cancer patients and is safe and feasible, warranting further research.</p> <p>Registration number.</p> <p>ChiCTR2300077008.</p> <p>Date of registration.</p> <p>October 26, 2023.</p>