Instrumented stabilization with intersomatic fusion can be achieved by open (O-TLIF) or minimally invasive (MIS-TLIF) transforaminal surgical access. While less invasive techniques have been associated with reduced postoperative pain and disability, increased manipulation and insufficient decompression may contradict MIS techniques. In order to detect differences between both techniques in the short-term, a prospective, controlled study was conducted. Thirty-eight patients with isthmic or degenerative spondylolisthesis or degenerative disk disease were included in this prospective, controlled study (15 MIS-TLIF group vs. 23 O-TLIF group) after failed conservative treatment. Patients were examined preoperatively, on the first, third, and sixth postoperative day as well as after 2, 4, and 12 weeks postoperatively. Outcome parameters included blood loss, duration of surgery, pre- and postoperative pain (numeric rating scale [NRS], visual analog scale [VAS]), functionality (Timed Up and Go test [TUG]), disability (Oswestry Disability index [ODI]), and quality of life (EQ-5D). Intraoperative blood loss (IBL) as well as postoperative blood loss (PBL) was significantly higher in the O-TLIF group ([IBL O-TLIF 528 ml vs. MIS-TLIF 213 ml, p = 0.001], [PBL O-TLIF 322 ml vs. MIS-TLIF 30 ml, p = 0.004]). The O-TLIF cohort showed significantly less leg pain postoperatively compared to the MIS-TLIF group ([NRS leg 3rd postoperative day, p = 0.027], [VAS leg 12 weeks post-op, p = 0.02]). The MIS group showed a significantly better improvement in the overall ODI (40.8 ± 13 vs. 56.0 ± 16; p = 0.05). After 3 months in the short-term follow-up, the MIS procedure tends to have better results in terms of patient-reported quality of life. MIS-TLIF offers perioperative advantages but may carry the risk of increased nerve root manipulation with consecutive higher radicular pain, which may be related to the learning curve of the procedure.