Severe periodontitis is challenging to treat. The aim of this study was to evaluate the efficacy of a combined Er:YAG laser (ERL) and Nd:YAG laser (NDL) in non-surgical treatment for severe periodontitis. One week after supragingival scaling, 32 systemically healthy patients with stage III or IV periodontitis were randomly divided into a control group (16 subjects) and a test group (16 subjects). The control group was treated by scaling and root planning (SRP) with ultrasonic equipment and manual instruments, and the test group was treated by SRP as well as ERL and NDL. Before treatment, the following clinical parameters were recorded at baseline: debris index (DI), probing depth (PD), clinical attachment level (CAL), and percentage of bleeding on probing (BOP %). Two months after therapy, the clinical parameters were recorded again, and the results between the groups were compared. All clinical parameters were significantly improved in both groups after therapy. For moderately deep periodontal pockets (4 mm ≤ PD ≤ 6 mm), the gains in CAL were greater in the test group (1.17 ± 1.47 mm) than in the control group (0.46 ± 2.78 mm), while no significant difference was found for PD reductions after therapy between the two groups. For deep periodontal pockets (PD > 6 mm), the differences in all of the clinical parameters were similar between the test group and the control group. In this short-term study, ERL and NDL radiation exhibited potential advantages in improving the clinical attachment level compared to conventional SRP in the non-surgical treatment of severe periodontitis.