Background/Objectives: Acute low back pain (LBP) is a prevalent cause of disability worldwide. If often involves both inflammation and reflex muscle spasm, suggesting combined therapy with a non-steroidal anti-inflammatory drug (NSAID) and a muscle relaxant may provide superior relief. This study aimed to evaluate the short-term efficacy and safety of a single intramuscular (IM) injection of a fixed-dose combination (FDC) product containing Diclofenac and Thiocolchicoside versus Diclofenac monotherapy in adults with acute LBP. Methods: We conducted a phase III multicenter, randomized, double-blind, parallel-group trial in 140 patients with acute LBP of moderate to severe intensity. Patients were allocated 1:1 to receive either the combination of Diclofenac sodium 75 mg + Thiocolchicoside 4 mg (FDC product, Test Group) or Diclofenac sodium 75 mg alone (Diclofenac monotherapy, Reference Group) via a single IM injection. The primary outcome was the change in patient-reported pain intensity using the Visual Analogue Scale (VAS) from baseline to 3 h post-dose. Key secondary outcomes included pain change at 1 h in the VAS, improvement in lumbar mobility (finger-to-floor distance test, FTF), the proportion of patients achieving >30% pain reduction, and the incidence of adverse events (AEs). Randomization was centralized and both investigators and patients were blinded to the treatment. Results: All 140 randomized patients completed the trial. At 3 h post-injection, the combination therapy produced a significantly greater mean pain reduction than monotherapy (41.52 mm vs. 28.13 mm on the 100 mm VAS; p < 0.0001). Superiority of the combination was already evident at 1 h post-dose (VAS reduction 27.61 mm vs. 20.40 mm; p = 0.0089). Lumbar flexion improved more with the combination at 3 h (mean FTF distance improvement 14.52 cm vs. 7.94 cm; p < 0.0001) and at 1 h (9.21 cm vs. 4.62 cm; p < 0.0001). A higher proportion of patients achieved >30% pain relief with the combination (45.7% vs. 27.2% at 3 h, p < 0.0001; 31.4% vs. 18.6% at 1 h, p = 0.0066). Only one mild, transient adverse event (headache) was reported in the combination group (1.4% of patients) and none in the diclofenac-only group. No serious AEs occurred. Conclusions: A single intramuscular dose of diclofenac plus thiocolchicoside provided faster, greater relief of acute LBP than diclofenac alone, without compromising safety. The combination therapy significantly reduced pain and muscle spasm-related mobility limitations within 1–3 h and was well tolerated. These results support the combined use of an NSAID and muscle relaxant as an effective and safe option for acute moderate-to-severe LBP management.