Objective To compare the effectiveness of unilateral biportal endoscopic transforaminal lumbar interbody fusion (UBE-TLIF) and endoscopic transforaminal lumbar interbody fusion (Endo-TLIF) in the treatment of single-segment degenerative lumbar spinal stenosis with lumbar spondylolisthesis. Methods Between November 2019 and May 2023, a total of 81 patients with single-segment degenerative lumbar spinal stenosis with lumbar spondylolisthesis who met the selection criteria were enrolled. They were randomly divided into UBE-TLIF group (39 cases) and Endo-TLIF group (42 cases). There was no significant difference in baseline data between the two groups (P>0.05), including gender, age, body mass index, surgical segment, and preoperative visual analogue scale (VAS) scores for low back and leg pain, Oswestry Disability Index (ODI), and serum markers including creatine kinase (CK) and C reactive protein (CRP). Total blood loss (TBL), intraoperative blood loss, hidden blood loss (HBL), postoperative drainage volume, and operation time were recorded and compared between the two groups. Serum markers (CK, CRP) levels were compared between the two groups at 1 day before operation and 1, 3, and 5 days after operation. Furthermore, the VAS scores for low back and leg pain, and ODI at 1 day before operation and 1 day, 3 months, 6 months, and 12 months after operation, and intervertebral fusion rate at 12 months after operation were compared between the two groups. Results All surgeries were completed successfully without occurrence of incision infection, vascular or nerve injury, epidural hematoma, dural tear, or postoperative paraplegia. The operation time in UBE-TLIF group was significantly shorter than that in Endo-TLIF group, but the intraoperative blood loss, TBL, and HBL in UBE-TLIF group were significantly more than those in Endo-TLIF group (P<0.05). There was no significant difference in postoperative drainage volume between the two groups (P>0.05). The levels of CK at 1 day and 3 days after operation and CRP at 1, 3, and 5 days after operation in UBE-TLIF group were slightly higher than those in the Endo-TLIF group (P<0.05), while there was no significant difference in the levels of CK and CPR between the two groups at other time points (P>0.05). All patients were followed up 12 months. VAS score of low back and leg pain and ODI at each time point after operation significantly improved when compared with those before operation in the two groups (P<0.05); there was no significant difference in VAS score of low back and leg pain and ODI between the two groups at each time point after operation (P>0.05). There was no significant difference in the intervertebral fusion rate between the two groups at 12 months after operation (P>0.05). ConclusionUBE-TLIF and Endo-TLIF are both effective methods for treating degenerative lumbar spinal stenosis with lumbar spondylolisthesis. However, compared to Endo-TLIF, UBE-TLIF requires further improvement in minimally invasive techniques to reduce tissue trauma and blood loss.