Abstract Smoking and diabetes mellitus (DM) are major risk factors for periodontitis, often leading to greater disease severity and reduced response to scaling and root planing (SRP). Consequently, adjunctive therapies have been explored to enhance treatment outcomes in these high‐risk populations. Given that periodontitis is an infectious‐inflammatory disease, both antimicrobial and host‐modulating agents have been proposed as adjuncts to support mechanical debridement. This narrative review critically evaluates clinical evidence from randomized clinical trials and systematic reviews assessing the efficacy of these adjuncts in the nonsurgical management of periodontitis in smokers and patients with DM. Local antimicrobials have shown site‐specific clinical benefits like probing depth reduction and clinical attachment gain, particularly in deep pockets, although microbiological evidence is limited. Systemic antimicrobials, particularly the amoxicillin‐metronidazole combination, demonstrated sustained clinical and microbiological improvements, especially in diabetic patients. Among host‐modulating strategies, sub‐antimicrobial dose doxycycline and locally delivered statins have shown promising effects, though high‐quality, long‐term evidence is still lacking. Adjunctive therapies may improve periodontal treatment outcomes in high‐risk populations, particularly in cases of severe disease. Nonetheless, significant heterogeneity in study design, outcome assessment, and risk factor control limits the generalizability of current findings. Future research should prioritize rigorous methodology, stratified analyses, and the use of clinically meaningful endpoints to better inform evidence‐based decisions on adjunctive therapies in patients with risk factors.