Purpose <p>This study aimed to evaluate whether systemic inflammatory markers—neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR)—can predict tumor response to neoadjuvant chemoradiotherapy (nCRT) in patients with rectal cancer.</p> Methods <p>A retrospective, single-center study included 396 patients with biopsy-proven rectal cancer (clinical stage T2–4NxM0 or any T N + M0) treated with curative intent. All patients underwent standardized nCRT, followed by either radical surgery with total mesorectal excision (TME) or non-operative management in cases of sustained complete clinical response (cCR). Pre-treatment NLR, PLR, and LMR were calculated from baseline blood counts. Tumor response was categorized using tumor regression grade (TRG): TRG 0 (complete response), TRG 1 (almost complete), TRG 2 (partial), and TRG 3 (no response).</p> Results <p>Incomplete responders (TRG 1–3) had higher NLR (<i>p</i> &lt; 0.001), PLR (<i>p</i> = 0.002), and carcinoembryonic antigen (CEA, <i>p</i> &lt; 0.001), and were more frequently male (<i>p</i> = 0.021). Complete responders (TRG 0) were more associated with higher LMR (<i>p</i> &lt; 0.001), elevated hemoglobin levels (<i>p</i> = 0.049), more comorbidities (<i>p</i> = 0.001), and greater use of antihypertensives (<i>p</i> = 0.012) and antiplatelet/anticoagulant drugs (<i>p</i> = 0.045). Risk estimates of incomplete response were as follows: NLR &gt; 2.08 (RR 2.30, 95% CI 1.60–3.31), PLR &gt; 129.36 (RR 1.79, 95% CI 1.25–2.05), and LMR &gt; 2.67 (RR 0.42, 95% CI 0.26–0.66).</p> Conclusion <p>Pre-treatment NLR, PLR, and LMR are predictors of response to nCRT in patients with rectal cancer. An NLR &gt; 2.08 is an independent predictor of incomplete response to nCRT. These findings contribute a cost-effective and readily available tool to the rectal cancer management arsenal.</p>