In this trial, the feasibility and efficacy of neoadjuvant chemotherapy with targeted agents in the treatment of patients with locally advanced rectal cancer were evaluated. In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. We performed a random assignment by a computer-generated random number sequence. The primary end point was the R0 resection rate. The secondary end points were rates of pathologic complete response, downstaging, adverse events, postoperative complications, preventive enterostomy and low anterior resection syndrome. From January 6, 2020 to October 28, 2022, 80 patients were assigned and evaluated. In the mFOLFOX6-RT and mFOLFOX6-Cet groups, the rate of R0 resection was 96.7 and 96.9% (p = 1.000); the rate of pathological complete response (pCR) was 23.3 and 21.9% (p = 0.891); and the rate of downstaging (ypStage 0 to 1) was 53.3 and 53.1% (p = 1.000), respectively. No statistical differences between the two groups were observed in the incidence of adverse events and postoperative complications. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.