Chemotherapy-induced peripheral neuropathy (CIPN) with restriction of daily activity (RDA) was common consequence of oxaliplatin-based chemotherapy in colorectal cancer patients. CIPN with RDA and negative mood may impact the quality of life (QoL). However, the relationships among RDA, mood, and QoL remain unclear. This was a cross-sectional relative study in which four instruments were used: the Neuropathic Pain Symptom Inventory was used to measure the severity of CIPN; the Screening of Activity Limitation and Safety Awareness scale was used to evaluate RDA; the Profile of Mood States Short Form was used to assess negative mood; and the Functional Assessment Cancer Center Therapy-Colorectal scale version 4 was used to evaluate QoL. Relationships among the variables were analyzed by bivariate correlation, hierarchical multiple linear regression, and Baron and Kenny's mediation testing. One hundred three colorectal adenocarcinoma patients with CIPN after receiving oxaliplatin-based chemotherapy were enrolled. Patients had mild-to-moderate CIPN and mild RDA. Significant correlations were found between CIPN and mood (r = 0.425, P < 0.001), between RDA and mood (r = 0.343, P < 0.001), and between RDA and QoL (r = 0.285, P < 0.01). RDA and mood may impact QoL. Under mediation effect analysis, mood mediated 38.48% of the effect of RDA on QoL (P < 0.001). Negative mood is the major factor impacting QoL in colorectal cancer patients with CIPN. Although the management of CIPN and RDA can prevent irreversible functional problems, enhancing the adaption of mood disturbance can strongly promote their QoL. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.