Background The 5-fluorouracil (5-FU), capecitabine-based long-course or short-course radiotherapy (SCRT) eventually preceded or followed by induction or consolidation chemotherapy (CT) and resection represents the preferred regimen for the treatment of locally advanced rectal cancer (LARC). This study aims to report our experience as a large medical center in Saudi Arabia, with the efficacy of short-course radiation therapy followed by oxaliplatin-based CT in achieving a pathologic complete response (pCR) in patients with LARC. Materials and methods This retrospective analysis encompassed 57 patients diagnosed with LARC at a large tertiary center in Riyadh, Saudi Arabia, from June 2020 to December 2022. All participants underwent short-term radiotherapy (25 Grays (Gy) over fractions within one week) followed by CT with 5-FU, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX), constituting the total neoadjuvant therapy (TNT). Surgical intervention and total mesorectal excision were performed six to eight weeks post-preoperative treatment. The primary endpoint was the pCR rate. Results Of the study participants, 34 (60%) were males, with a mean age of 57.6 ± 13.9 years. Two-thirds (n = 37,65%) were classified as T3. The overall response rates were 12 (21%), 12 (21%), 24 (42%), and nine (16%), for complete response (CR), near-complete response (nCR), partial response (PR), and progressive disease (PD), respectively. The multivariable logistic regression model identified five independent predictors for overall CR after adjusting for disease-related factors: N-stage, the circumferential resection margin (CRM), average vascularity (AV), surgical procedure, and postoperative tumor size. Patients with N2 disease had an 18% lower chance of achieving CR (OR = 0.824
95% CI: 0.634-0.974
p = 0.035). Positive CRM was linked to a 71% reduction in the probability of CR (OR = 0.268
95% CI: 0.087-0.823
p = 0.021). Each 1 cm increase in AV corresponded to a 28.5% increase in the likelihood of complete response (OR = 1.285
95% CI: 1.029-1.605
p = 0.027). Patients who underwent AR had 2.8 times greater chances of achieving CR than those who underwent abdominoperineal resection (APR) (OR = 2.801
95% CI: 1.057-9.324
p = 0.044). Lastly, each 1 cm increase in postoperative tumor size was associated with a 92.5% reduction in the odds of CR (OR = 0.074
95% CI: 0.017-0.330
p = 0.001). Conclusions The current study supports the efficacy of TNT for treating LARC, with a pCR rate of 21% and near-complete response in nearly half of the patients with LARC. Significant predictors of pCR included N-stage, CRM status, AV size, and surgical approach. These insights could refine patient selection for TNT and inform future strategies to optimize treatment outcomes in rectal cancer. Prospective multicenter studies are warranted.