Objective: The study aims to compare the application value of midline catheter and indwelling needle in patients with oral cavity malignancies during perioperative period. Methods: 146 patients with oral cavity malignancies admitted to our hospital from January 2019 to July 2021 were selected as the research subjects. 73 patients treated with midline catheters during the treatment were the experimental group, and another 73 patients were treated with indwelling needles as the control group. The indwelling time, total number of puncturing times, and incidence of adverse reactions of two catheterization methods were compared between the two groups. Meanwhile, each patient was investigated for treatment satisfaction. Result: The indwelling time was significantly longer in the experimental group than in the control group (P < 0.0001), and the total number of puncturing times in the experimental group was significantly lower than that in the control group (P < 0.0001). The incidence of adverse reactions in the experimental group (χ² = 4.960, P = 0.0259) was significantly lower than that in the control group in terms of catheter occlusion (χ² = 12.56, P = 0.0004), catheter detachment (χ² = 8.46, P = 0.0036), drug extravasation (χ² = 3.27, P = 0.0011), phlebitis (χ² = 3.62, P = 0.0003), and bleeding from the puncture point (χ² = 14.98, P = 0.0001). The satisfaction rate (χ² = 33.45, P < 0.0001) and fundamental satisfaction rate (χ² = 16.57, P < 0.0001) in the experimental group were significantly higher than those in the control group, while the dissatisfaction rate was significantly lower than that in the control group (χ² = 11.38, P = 0.0007). The difference is statistically significant. Conclusion: Compared with indwelling needle, the application of midline catheters in patients with oral cavity malignancies during perioperative period can effectively reduce the number of puncturing times and the incidence of catheter-related adverse reactions, with a high satisfaction rate, which is worthy of clinical promotion and application.