Background: Both physical activity and low-level laser therapy (LLLT) can reduce knee osteoarthritis (KOA) inflammation. We conducted a randomized clinical trial to investigate the short-and long-term effectiveness of LLLT combined with strength training in persons with KOA. Methods: Fifty participants were randomly divided in two groups, one with LLLT plus strength training (n = 26) and one with placebo LLLT plus strength training (n = 24). LLLT and strength training were performed triweekly for 3 and 8 weeks, respectively. In the laser group, 3 joules 904 nm wavelength laser was applied to fifteen points (45 joules) per knee per session. Patient-reported outcomes, physical tests, and ultrasonography assessments were performed at baseline and 3, 8, 26, and 52 weeks after initial LLLT or placebo therapy. The primary outcomes were pain on movement, at rest, at night (Visual Analogue Scale), and globally (Knee injury and Osteoarthritis Outcome Score (KOOS) subscale). Parametric data were assessed with analysis of variance using Šidák’s correction. Results: There were no significant between-group differences in the primary outcomes. However, in the laser group there was a significantly reduced number of participants using analgesic and non-steroidal anti-inflammatory drugs and increased performance in the sit-to-stand test versus placebo-control at week 52. The joint line pain pressure threshold (PPT) improved more in the placebo group than in the laser group, but only significantly at week 8. No other significant treatment effects were present. However, pain on movement and joint line PPT were worse in the placebo group at baseline, and therefore, it had more room for improvement. The short-term percentage of improvement in the placebo group was much higher than in similar trials. Conclusions: Pain was reduced substantially in both groups. LLLT seemed to provide a positive add-on effect in the follow-up period in terms of reduced pain medication usage and increased performance in the sit-to-stand test.