Objective: To observe and discuss the clinical effect of collagenase lysis in the treatment of lumbar disc herniation through different administration routes. Methods: Sixty patients with lumbar disc herniation admitted to Liuzhou People’s Hospital from February 2023 to February 2024 were selected, including 31 males and 29 females. They were divided into A and B groups according to the random number table method. Group A was injected through sacral hiatus route combined with intervertebral foramen safety triangle route (n = 30), and Group B was injected only through sacral hiatus route (n = 30). The VAS score, ODI index, and the efficacy of Macnab were observed before operation, 3 days, 1 month, and 3 months after operation, and the results were summarized and compared. Results: Compared with Group B (only through the sacral hiatus route), the VAS score, ODI index, and the efficacy evaluation of Macnab in Group A (through the sacral hiatus route combined with the intervertebral foramen safety triangle route) were significantly better, and the differences were statistically significant (P < 0.05). Conclusion: Multi-path collagenase lysis is more effective than single-path collagenase lysis.