Objective: To compare the effectiveness of premedication with Ibuprofen and Dexamethasone on the success rate of inferior alveolar nerve block in patients with irreversible pulpitis. Methods and analysis: This Randomized Controlled trial recruited patients of either gender between the ages of 18-60 years, presenting with pain (VAS≥114) in a mandibular molar with irreversible pulpitis. Additionally, they were not taking any antibiotics, anti-inflammatory or analgesics for at least one-week prior to treatment. Sixty participants were randomly assigned to two groups using the lottery method; Group A (Ibuprofen 400 mg) and Group B (Dexamethasone 0.5mg), with 30 patients in each group. All patients received the standard treatment i.e. IANB (1.8 ml of 2% lidocaine with 1:80000 epinephrine). The medications were given orally one hour prior to Inferior alveolar nerve block injections (IANB). Pain intensity was assessed four hours post treatment. SPSS version-26 was used for descriptive and inferential statistics by considering p<0.05. Results: Out of the sixty patients, 33(55%) were male and 27(45%) females with a mean age of 32.02± 6.6 years. After treatment, 30% of the patients (n=9) reported complete resolution of pain in the Dexamethasone group but none of the patients from the Ibuprofen group reported with no pain. Severe pain was experienced by only 7%(n=2) patients of Dexamethasone group while 30%(n=9) patients of Ibuprofen group conveyed severe pain (p=0.001). Dexamethasone is 66.6% sensitive and 80% specific; however, Ibuprofen is 20% sensitive and 33.3% specific in reducing the pain of the patients. Conclusion: Oral premedication with Dexamethasone resulted in a significantly higher success rate of inferior alveolar nerve block compared with Ibuprofen, in patients with irreversible pulpitis. Ibuprofen specifies lower effectiveness in reducing pain when compared with dexamethasone.