Objective: This study aims to evaluate the short- and long-term outcomes—specifically in terms of pain, disability, and quality of life—between minimally invasive surgery (MIS) and open transforaminal lumbar interbody fusion (TLIF) for treating lumbar spondylolisthesis. Study Design and Setting: A prospective cohort study was carried out at Liaquat National Hospital & Medical College, Karachi, and a teaching institution in South Asia. The study included patients with chronic back pain for over three months, unresponsive to medical treatment or accompanied by radicular symptoms, with MRI-confirmed grade I and II degenerative lumbar spondylolisthesis, lateral recess stenosis, and unilateral disc herniation. Patients with spinal metastasis, previous surgeries, inflammatory arthritis, or metabolic bone diseases were excluded. Methodology: The outcomes of MIS-TLIF and open-TLIF were assessed using the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and SF-36 quality of life scores at 1, 6, and 24 months postoperatively. Results: Among 93 patients, 35 underwent open-TLIF and 58 received MIS-TLIF. MIS-TLIF resulted in significantly less blood loss and faster recovery. At four weeks, the MIS group had lower VAS and ODI scores, and higher SF-36 scores. Similar trends continued at six months, with improvements in ODI and SF-36. By 24 months, the MIS group maintained lower ODI scores, though VAS and SF-36 scores were comparable. Conclusion: MIS-TLIF shows superior outcomes, especially in the early postoperative phase, with reduced morbidity and improved quality of life, making it a preferable option in resource-limited settings.