Objectives To compare the analgesic efficacy and tolerability of tramadol/dexketoprofen 75/25 mg (TRAM/DKP) versus diclofenac/thiocolchicoside 75/4 mg (DIC/THIO) in patients with moderate-to-severe acute low back pain (LBP). Methods Single-centre, observational study in 82 adult outpatients with LBP due to disc herniation (≥4 Numerical Rating scale, NRS) who received either oral TRAM/DKP (n = 44) or intramuscular DIC/THIO (n = 38), both given every 12 h for 5 days. The primary endpoint was the change from baseline in pain intensity (PI) at pre-specified post-dose time points (t day1, t day3, t day7) and compared between the two treatments. Additional endpoints, all evaluated at day 7, included: the sum of PI difference (SPID), percentage of responders in terms of PI reduction versus baseline and change from baseline in Douleur Neuropathique (DN4) score. Tolerability and safety were also assessed. Results Both treatment groups were comparable for demographic characteristics and comorbidities. Over the 5-day treatment period and up to day 7, compared to DIC/THIO, TRAM/DKP provided a significantly greater and sustained analgesia at day 3 and day 7 (p < .0001), with a higher proportion of responders at each time point [75% versus 71.1% (p = 0.687) at day 1, 93.2% versus 73.7% at day 3 (p = .016) and 95.5% versus 71.1% at day 7 (p = .003)], higher values of SPID (770.9 ± 23.5 vs. 507.1 ± 22.6; p < .0001) and significantly greater reduction in DN4 score [–62.7 ± 25.6 vs. −39.7 ± 31.2 (p < .0001)]. Both treatments were well tolerated. Conclusions Orally administered TRAM/DKP 75/25 mg can be a valuable and effective option in patients with acute LBP.