Introduction Oxaliplatin is an anticancer drug used primarily for cancers of the gastrointestinal tract, and oxaliplatin hypersensitivity reaction is a rare but serious side effect. This study aimed to identify the clinical characteristics and risk factors for oxaliplatin hypersensitivity reactions in patients with colorectal cancer. Methods This retrospective study included 280 patients who developed oxaliplatin hypersensitivity reactions and 476 patients who did not. Results Logistic regression analysis indicated that a history of allergy (odds ratio (OR) = 2.232, 95% confidence interval (CI) (1.209, 4.119), P = .010), previous oxaliplatin exposure (OR = 8.081, 95% CI (3.024, 21.593), P < .001), and chemotherapy regimen (OR = 2.148, 95% CI (1.411, 3.271), P < .001) were risk factors for oxaliplatin hypersensitivity reactions. These reactions averaged 7.29 ± 2.78 (median 7, 1–16) cycles, with a mean cumulative dose of 589.53 ± 274.43 mg. Grade 2 oxaliplatin hypersensitivity reactions were the most common, occurring in 197 patients (70.4%), followed by grade 3 reactions in 68 patients (24.3%), and grade 4 reactions in 9 patients (3.2%). The most common symptom of oxaliplatin hypersensitivity reactions was itching (211 patients, 75.4%), followed by facial flushing (133 patients, 47.5%), and chest discomfort (77 patients, 27.5%). Conclusions We identified a history of allergy to previous oxaliplatin exposure and chemotherapy regimens as risk factors for oxaliplatin hypersensitivity reactions. Healthcare providers should be aware of the risk factors for oxaliplatin hypersensitivity reactions and carefully monitor patients receiving oxaliplatin.