The aim of this study is to analyze surgical and functional outcomes in order to verify the applicability of surgical treatment guidelines as foreseen by MASCC/ISOO/ASCO 2019. Patients affected by stage 2 MRONJ refractory to conservative management were grouped if underwent surgical resection (Group A) or debridement (Group B). Health-related quality of life was evaluated by using the European Organization for Research and Treatment of Cancer questionnaires, QLQ-C30 and H&N35. Statistical analysis was performed using Wilcoxon/Mann–Whitney test, Kaplan–Meier test, Cox regression model and Cox multivariate regression. Group A showed higher complete healing cases vs. group B. Recurrence rate difference in group A vs. group B was statistically significant. Debridement is an unfavorable prognostic factor when compared to surgical resection (p = 0.0032, HR 4.9). Quality of life mean values showed a marked improvement in Group A and a slight improvement in Group B. Debridement has 4.9 times more risk to develop recurrence when compared to surgical resection. A more satisfactory quality of life was shown in patients subject to resective surgery with an improving trend from baseline. Debridement patients showed more variability of results and an overall negative trend at the end of the 6-month follow-up.