Background and Objective:To analyze the effects of several drug for pain prevention in adults undergoing craniotomy for elective brain surgery.Material and Methods:A systematic review and meta-analysis were conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The inclusion criteria were limited to randomized controlled trials (RCTs) that evaluated the effectiveness of pharmacological treatments for preventing post-operative pain in adults (aged 18 years or older) undergoing craniotomies. The main outcome measures were represented by the mean differences in validated pain intensity scales administered at 6 h, 12 h, 24 h and 48 h post-operatively. The pooled estimates were calculated using random forest models. The risk of bias was evaluated using the RoB2 revised tool, and the certainty of evidence was assessed according to the GRADE guidelines.Results:In total, 3359 records were identified through databases and registers’ searching. After study selection, 29 studies and 2376 patients were included in the meta-analysis. The overall risk of bias was low in 78.5% of the studies included. The pooled estimates of the following drug classes were provided: NSAIDs, acetaminophen, local anesthetics and steroids for scalp infiltration and scalp block, gabapentinoids and agonists of adrenal receptors.Conclusions:High-certainty evidence suggests that NSAIDs and acetaminophen may have a moderate effect on reducing post-craniotomy pain 24 h after surgery compared to control and that ropivacaine scalp block may have a bigger impact on reducing post-craniotomy pain 6 h after surgery compared to control. Moderate-certainty evidence indicates that NSAIDs may have a more remarkable effect on reducing post-craniotomy pain 12 h after surgery compared to control. No moderate-to-high-certainty evidence indicates effective treatments for post-craniotomy pain prevention 48 h after surgery.