Background: Long-term clinical outcomes with microendoscopic spine surgery (MESS) are poorly investigated. The effect of instrument angulation on clinical outcomes has yet to be assessed. Methods: A total of 229 consecutive patients operated on via two MESS systems were analyzed. Instrument angulation for both MESS systems, which differ from each other regarding the working space for instruments, was assessed using a computer model. Patients’ charts and endoscopic video recordings were reviewed to determine clinical outcomes, complications, and revision surgery rates. At a minimum follow-up of two years, clinical outcomes were assessed employing the Neck Disability Index (NDI) and Oswestry Disability Index (ODI). Results: A total of 52 posterior cervical foraminotomies (PCF) and 177 lumbar decompression procedures were performed. The mean follow-up was six years (range 2–9 years). At the final follow-up, 69% of cervical and 76% of lumbar patients had no radicular pain. The mean NDI was 10%, and the mean ODI was 12%. PCF resulted in excellent clinical outcomes in 80% of cases and 87% of lumbar procedures. Recurrent disc herniations occurred in 7.7% of patients. The surgical time and repeated procedure rate were significantly lower for the MESS system with increased working space, whereas the clinical outcome and rate of complication were similar. Conclusions: MESS achieves high success rates for treating degenerative spinal disorders in the long term. Increased instrument angulation improves access to the compressive pathology and lowers the surgical time and repeated procedure rate.