Background: Regorafenib (R) and Trifluridine/Tipiracil ± bevacizumab (T) are approved for treating refractory metastatic colorectal cancer (mCRC) but their optimal sequence is unclear. This study describes the characteristics/clinical outcomes of patients with mCRC in U.S. clinical practice treated sequentially with R-T or T-R. Methods: A retrospective cohort study of 818 patients treated with R-T or T-R between January 2015 and November 2022 was conducted using an electronic health record-derived database. The primary objective was to describe the demographic/clinical characteristics and biomarker status of patients treated with R-T or T-R, stratified by treatment line/age. Secondary objectives were to evaluate/estimate the frequency of neutropenia and myelosuppression-related treatments, the number/type of subsequent therapies, time to treatment discontinuation (TTD), and overall survival (OS). Results: Baseline characteristics were similar among patients who received R-T (n = 393) or T-R (n = 425). Lower rates of moderate/severe neutropenia (26%/12% vs. 32%/16%) and granulocyte colony-stimulating factor/erythropoietin use (22% vs. 24%) were observed with R-T versus T-R. The median TTD was 8.7 months and 8.5 months with R-T versus 8.1 months and 7.9 months with T-R as third- and fourth-line treatment, respectively. The median OS was 13.1 months and 11.6 months with R-T versus 11.5 months and 10.3 months with T-R as third- and fourth-line treatment, respectively. Conclusions: This study did not show a statistically significant difference in OS with R-T versus T-R. Although limited by its retrospective nature, the study suggested R-T may be preferable to T-R given the observed reduction in neutropenia/myelosuppression-related treatments.