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Background: Total neoadjuvant therapy is becoming a preferred option for locally advanced rectal cancer, particularly in patients with high-risk baseline features. However, real-world evidence comparing tumor response, MRI-defined high-risk feature clearance, surgical outcomes, and survival after total neoadjuvant therapy versus conventional long-course chemoradiotherapy remains limited. This study aimed to compare outcomes between total neoadjuvant therapy and long-course chemoradiotherapy in patients with locally advanced rectal cancer treated in routine clinical practice. Methods: This is a retrospective, single-centre cohort study focused on patients with stage II-III locally advanced rectal adenocarcinoma treated with curative-intent neoadjuvant therapy using either total neoadjuvant therapy or long-course chemoradiotherapy. Tumor response was assessed using restaging MRI, clinical complete response, and pathological complete response. Surgical outcomes and overall survival were evaluated. Results: A total of 110 patients were included. Patients treated with total neoadjuvant therapy had a higher baseline disease burden reflected by a greater proportion of cT4 tumors (40.6% vs. 19.2%; p = 0.014). Radiologic tumor-length response and clearance of MRI-defined high-risk features were comparable between treatment strategies. Clinical and pathological complete response rates were numerically higher in the total neoadjuvant therapy group, but the differences were not significant (cCR: 15.6% vs. 6.4%, p = 0.151; pCR: 18.5% vs. 9.7%, p = 0.301). Conclusions: In this real-world cohort, TNT was preferentially used in patients with more advanced baseline disease and showed numerically higher complete response rates, although differences were not statistically significant. Radiologic response, surgical outcomes, and short-term survival were comparable between treatment strategies. These findings support the feasibility of TNT in routine clinical practice but should be interpreted as exploratory and hypothesis-generating rather than evidence of treatment superiority.