Negative Pressure Wound Therapy (NPWT) is a standard treatment for chronic wounds. In 2017, NPWT with instillation and dwell time (NPWTi-d) was approved for insurance coverage in Japan. This study aimed to identify optimal NPWTi-d parameter settings for hard-to-heal wounds with necrotic tissue. We conducted a retrospective observational study of consecutive patients treated with NPWTi-d between August 2017 and February 2019. Parameters analyzed included dressing change frequency (three times per week vs. once per week), therapy duration (2, 3, or 3.5 h), negative pressure levels (50–125 mmHg), dwell time (1–10 min), and instillation volume (mL/cm3 of foam). Fifty-six patients were included. Among the 52 patients managed with once-weekly dressing changes, five developed infections. A dwell time of ≥ 5 min significantly shortened the median treatment period to 11 days, compared to 26 days in those with shorter dwell times. NPWTi-d is more effective when treatment parameters are optimized. A dwell time over 5 min and once-per-week dressing replacement are sufficient, reducing both patient burden and healthcare provider workload. These findings provide evidence-based guidance for the efficient clinical use of NPWTi-d.