Background: Oral-pigmented lesions have raised aesthetic concerns, leading to multiple depigmentation techniques. This systematic review and network meta-analysis aimed to assess the efficacy of different treatments for oral hyperpigmentation. Methods: A computerized search was conducted on Science Direct, Medline via PubMed, Scopus, and Web of Science using the relevant keywords. English-language studies published between 2013 and 2023 that focused on patients with oral pigmented lesions subjected to different treatment modalities, such as laser or surgical intervention, were compared to determine their efficacy and safety profile. Data were analyzed using R software, applying frequentist models. Results: A total of 27 studies were included. In contrast to the CO2 laser, Er: YAG laser was linked to a higher risk of bleeding (RR = 2.73, p < 0.01), whereas the diode laser had the most favorable score in minimizing bleeding index (P-score = 0.86). In terms of lower risk and postoperative pain score (RR = 0.01, p < 0.01), the Er,Cr:YSGG laser had the most favorable result (P-score = 1.00). The Er: YAG laser demonstrated the highest probability of preventing recurrence (RR = 0.28, p < 0.01), followed by the diode laser (RR = 0.42, p < 0.01). Conclusions: The choice of treatment for oral pigmentation should be based on individual patient needs and the desired outcomes. The Er: YAG laser seems highly effective in preventing pigment recurrence, the diode laser emerges as a top contender in managing bleeding risks, and the Er,Cr:YSGG laser is particularly efficacious in managing postoperative pain.