Background: The aim of this systematic review is to evaluate and synthesize scientific evidence on the effect of surgical interventions for removal of mandibular third molar (M3M) on periodontal healing of adjacent mandibular second molar (M2M).Methods: The protocol was registered at PROSPERO (International Prospective Register of Systematic Reviews) as CRD42012003059. Medline, Cochrane, and EMBASE databases were interrogated to identify randomized controlled trials (RCTs) up to December 22, 2014. Patients with M3Ms fully developed, unilaterally or bilaterally impacted, were considered. Outcomes were clinical attachment level gain (CALg) and probing depth reduction (PDr) with a follow‐up ≥6 months. Patient‐subjective outcomes, such as pain, discomfort, and complications, and financial aspects and chair time, were also explored. A Bayesian network meta‐analysis model was used to estimate direct and indirect effects and to establish a ranking of treatments.Results: Sixteen RCTs were included and categorized into four groups investigating the following: 1) regenerative/grafting procedures (10 RCTs); 2) flap design (three RCTs); 3) type of suturing (one RCT); and 4) periodontal care of M2M (two RCTs). Guided tissue regeneration (GTR) with resorbable (GTRr) and non‐resorbable (GTRnr) membrane and GTRr with anorganic xenograft (GTRr + AX) showed the highest mean ranking for CALg (2.99, 90% credible interval [CrI] = 1 to 5; 2.80, 90% CrI = 1 to 6; and 2.29, 90% CrI = 1 to 6, respectively) and PDr (2.83, 90% CrI = 1 to 5; 2.52, 90% CrI = 1 to 5; and 2.77, 90% CrI = 1 to 6, respectively). GTRr + AX showed the highest probability (Pr) of being the best treatment for CALg (Pr = 45%) and PDr (Pr = 32%). Direct and network quality of evidence were rated from very low to moderate.Conclusions: To the best of the authors’ knowledge, the present review is the first one to evaluate quantitatively and qualitatively the effect of different interventions on periodontal healing distal to the second molar after extraction of the third molar. GTR‐based procedures with or without combined grafting therapies provide some adjunctive clinical benefit compared to standard non‐regenerative/non‐grafting procedures. However, the overall low quality of evidence suggests a low degree of confidence and certainty in treatment effects. Evidence on variations of surgical M3M removal techniques based on flap design, type of suturing, and periodontal care of M2M is limited both qualitatively and quantitatively.