Purpose The aim of this study is to investigate the clinical outcomes of transforaminal lumbar endoscopic discectomy (TLED) in patients with L5-S1 lumbar disc herniation (LDH). Materials and methods Seventy-five consecutive individuals with diagnosed foraminal/extraforaminal L5-S1 LDH were included in this study. All patients underwent TLED, being subsequently evaluated in a 2-year follow-up period. Assessment was performed preoperatively and at 6 weeks and 3, 6, 12 and 24 months postoperatively. Visual Analogue Scale (distinctly applied for lower limb – VAS-LP and low back – VAS-BP pain) and Short-Form 36 (SF-36) Medical Health Survey Questionnaire were implemented to assess pain and health-related quality of life (HRQoL) of enrolled individuals, respectively. Results No major perioperative complications were observed. Recorded values of all studied indices were demonstrated to feature a clinically and statistically significant amelioration at 6 weeks, presenting lesser improvement at 3 months with subsequent stabilisation. VAS-LP and VAS-BP values were displayed to reach a plateau in 6 months postoperatively, whereas all parameters of SF-36 continued to present a statistically significant improvement until the end of follow-up at 2 years. Conclusions TLED represent a safe and efficient technique in terms of diminishing perceived pain and improving HRQoL in patients with L5-S1 LDHs. However, specific patient- and technique-related circumstances on the ground of low surgical experience may limit its effectiveness in these patients.