Erectile dysfunction (ED) affects one in five men, with moderate to severe forms disproportionately prevalent among men with type 2 diabetes mellitus (T2DM). First-line phosphodiesterase 5 inhibitors (PDE5i) fail in 30-35% of men, and no single non-invasive treatment reliably restores penetrative function in this refractory population. This retrospective case series reports a multimodal protocol in 71 hypogonadal men (38 euglycemic, 33 T2DM) with moderate to severe ED (Erection Hardness Score [EHS] ≤2) refractory to maximum-dose PDE5i. All men received shockwave therapy, class IV laser, therapeutic ultrasound, therapeutic exercise, daily tadalafil, testosterone cypionate, and counseling addressing psychological contributors to ED. Men with T2DM also received tirzepatide (Mounjaro, 2.5-7.5 mg weekly) over the 3-4 month treatment period. Every man improved from an EHS ≤2 to ≥3, restoring penetrative intercourse, with 68% of euglycemic men and 58% of men with T2DM reaching EHS 4. Arizona Sexual Experience Scale scores improved by a median of 6 points in both groups, and PROMIS-10 scores improved, with baseline between-group differences eliminated after treatment. Despite greater baseline severity, men with T2DM achieved equivalent post-treatment sexual function. In this group, hemoglobin A1c fell from 9.2% to 6.2%, with 58% transitioning from the diabetic to the prediabetic range. Both groups lost fat while gaining skeletal muscle and grip strength, with larger changes in men with T2DM, indicating that concurrent testosterone and resistance exercise counteracted the muscle loss typically associated with incretin therapy. These findings suggest that refractory ED, particularly with diabetes and hypogonadism, may require simultaneous intervention across multiple pathophysiologic domains rather than sequential escalation of single-modality treatments. Prospective controlled trials are needed to confirm these findings and determine the contribution of each component.