Objectives: To assess the effect of oxygen-ozone therapy guided by percutaneous Computed Tomography (CT) compared to corticosteroids in individuals experiencing lower back pain (LBP) not attributed to underlying bone-related issues. Methods: A total of 321 patients (192 males and 129 females, mean age: 51.5 ± 15.1 years) with LBP were assigned to three treatment groups: group A) oxygen-ozone only, group B) corticosteroids only, group C) oxygen-ozone and corticosteroids. Treatment was administered via CT-guided injections to the intervertebral disc (i.e., intradiscal location). Clinical improvement of pain and functionality was assessed via self-reported pain scales and magnetic resonance (MR) and CT imaging. Results: At all follow-up times, the mean score of the numeric rating scale and the total global pain scale (GPS) of study groups receiving oxygen-ozone (groups A and C) were statistically significantly lower than the study group receiving corticosteroids only (group B), with p < 0.001. There was a statistically significant difference between groups A and C at 30 days for the numeric rating scale. Conclusions: The percutaneous application of oxygen-ozone in patients with LBP due to degeneration of the lumbosacral spine showed long-lasting significant pain reduction of up to two years post-treatment when compared to corticosteroids alone. Combination therapy of oxygen-ozone and corticosteroids can be useful as corticosteroids showed statistically significant improvement in LBP earlier than the oxygen-ozone-only treatment.