We describe the case of a 68-year-old woman with an acute episode of severe low back pain (LBP) resistant to opioids, who had experienced a sacral insufficiency fracture (SIF) two years earlier. At clinical examination, patient reported constant, dull, non-localizable pain at lumbar and sacral level, exacerbated by paravertebral palpation, particularly at L4-L5 and the sacroiliac joint, with a concomitant and remittent neuropathic component, difficult to localize at lumbar and sacral level. The latest magnetic resonance imaging study revealed disc herniations at L3-L4, L4-L5, and L5-S1 levels. The patient was treated with intramuscularparavertebral injections of oxygen-ozone (O2O3) mixture for 4 weeks (once a week), using a O3 concentration of 20 mcg/mL (5 mL in L4-L5 zone and 5 mL in L5-S1 zone, bilaterally). At 1 week after the first injection, the pain (assessed by Numerical Pain Rating Scale and Brief Pain Inventory) was considerably reduced and the patient's health-related quality of life (assessed by Short Form 12-Item Health Survey and European Quality of Life Index) had improved; these findings were confirmed at follow-up 1 month after the last injection. This paradigmatic case of nociplastic pain successfully treated by paravertebral O2O3 therapy might be a starting point for further studies on the effects of this treatment in terms of decreasing pain and improving HRQoL in patients affected by opioid-resistant LBP.