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This systematic review (SR; PROSPERO database: CRD42017075160) and network meta-analysis (NMA) identified the most effective oral premedication for anaesthetic success of inferior alveolar nerve blocks (IANB) in cases of irreversible pulpitis. Medline and Ebscohost databases were searched up until 10/2017. Randomized controlled trials (RCT) studying the effect of oral premedication, alone or in combination, on the success of IANB for cases of irreversible pulpitis, compared to placebo or other oral premedications, were included. Quality of the included studies was appraised by the revised Cochrane risk of bias tool for randomized trials. Pairwise analysis, NMA and quality of evidence assessment using GRADE criteria were performed. Nineteen studies (n = 1654 participants) were included. NMA demonstrated that compared to placebo, dexamethasone was most effective in increasing anaesthetic success (RR, 2.92 [95% CI 1.74,4.91]; SUCRA = 0.96), followed by NSAIDs (RR, 1.92 [95% CI 1.63,2.27], SUCRA = 0.738) and Tramadol (RR, 2.03 [95% CI 1.18,3.49], SUCRA = 0.737). Premedication with acetaminophen added to NSAIDs demonstrated similar efficacy as NSAIDs alone (RR, 1.06 [95% CI 0.79,1.43]). Sensitivity analyses proved the superiority of dexamethasone or NSAIDs over any other premedications. Subgroup analyses of specific dosages in comparison with placebo demonstrated that dexamethasone 0.5 mg was most effective, followed by ketorolac 10 mg, piroxicam 20 mg, ibuprofen 400 mg + acetaminophen 500 mg and Tramadol 50 mg. Ibuprofen 400 mg, 600 mg and 800 mg had a significantly improved IANB success, while Ibuprofen 300 mg had no effect. Oral premedication with dexamethasone, NSAIDs or Tramadol significantly increased anaesthetic success. More trials are needed to evaluate the premedication effects of dexamethasone or Tramadol for improved anaesthetic success of IANB when treating irreversible pulpitis.