(1) Background: Severely compromised teeth affected by endo-periodontal lesions are often assigned a "hopeless" prognosis, however, there is only limited evidence available. (2) Methods: In a retrospective study, we evaluated the long-term effectiveness of combined endodontic and regenerative periodontal therapy in teeth with advanced endo-periodontal lesions: 35 patients (age 47-83 years) with a total of 39 teeth diagnosed with grade 3 endo-periodontal lesions were treated by endodontists using an operating microscope followed by regenerative periodontal surgery. (3) Results: Changes in radiographic bone levels (rBl) and probing pocket depths (PPDs) were evaluated after 1 year (T) and up to 7 years postoperatively (T). Mean rBL gain was significant with 4.87 ± 3.47 mm after 1 year (T) and stable results with a mean rBL gain of 4.70 ± 3.37 mm at T. Mean PPD was significantly reduced from 9.74 ± 2.05 mm at baseline to 5.04 ± 1.61 mm at T and to 4.87 ± 2.32 mm at T. Tooth loss amounted to 10.3% ( = 4) and was due to root fracture. (4) Conclusion: The results suggest that the combined endodontic and regenerative periodontal therapy of endo-periodontal lesions of "hopeless" teeth can lead to favorable long-term results with tooth retention for up to 7 years.