Objectives The aim of this systematic review was to investigate the association between the intake of systemic medications that may affect bone metabolism and their subsequent impact on implant failures. Material and methods Electronic and manual literature searches were conducted. Implant failure (IF) was the primary outcome, while biological/mechanical and the causes/timing associated with IF were set as secondary outcomes. Meta‐analyses for the binary outcome IF and odds ratio were performed to investigate the association with medications. Results A final selection of 17 articles was screened for qualitative assessment. As such, five studies focused on evaluating the association of implant failure and non‐steroidal anti‐inflammatory drugs (NSAIDs), two on selective serotonin reuptake inhibitors (SSRIs), two on proton pump inhibitors (PPIs), seven on bisphosphonates (BPs), and one on anti‐hypertensives (AHTNs). For PPIs, the fixed effect model estimated a difference of IF rates of 4.3%, indicating significantly higher IF rates in the test compared to the control group ( p < 0.5). Likewise, for SSRIs, the IF was shown to be significantly higher in the individuals taking SSRIs ( p < 0.5) as estimated a difference of 7.5%. No subset meta‐analysis could be conducted for AHTNs medications as only one study fulfilled the inclusion criteria, which revealed an increased survival rate of AHTN medication. None of the other medications yielded significance. Conclusions The present systematic review showed an association of PPIs and SSRIs with an increased implant failure rate. Hence, clinicians considering implant therapy should be aware of possible medication‐related implant failures.