Impacts caused by cancer and associated treatment may change with time. The objective of this study is to examine the change trajectory of symptom distress, coping strategies, and spiritual wellbeing in colorectal cancer patients during chemotherapy and to further examine the predictors of spiritual wellbeing. A prospective longitudinal repeated measures study design was employed. A total of 97 patients undergoing chemotherapy for the first time were enrolled. A structured questionnaire was used to collect data at three timepoints, which were before chemotherapy (T0), during chemotherapy (T1: 3 months after T0), and after chemotherapy (T2: 6 months after T0). The results of this study show that patients have significantly lower spiritual wellbeing and significantly higher symptom distress during chemotherapy treatment (T1). Family support (B = 0.39, p = 0.007) and problem-focused coping strategies (B = 0.47, p = 0.001) are significant predictors of spiritual wellbeing before chemotherapy (T0). Symptom distress (B = −0.18, p = 0.048) and problem-focused coping strategies (B = 0.26, p = 0.028) are significant predictors of spiritual wellbeing during chemotherapy (T1). The results provide care recommendations for different stages of chemotherapy to help to achieve more precise patient care and improve care quality.