Purpose <p>To assess the effect of collagen plug application into the alveolar socket following surgical extraction of impacted lower third molars (IL3rdM) on pain, mouth opening, and the incidence of Alveolar Osteitis (AO).</p> Materials and methods <p>A split-mouth randomized controlled trial was conducted on patients with bilaterally partially IL3rdM. Similar surgical extraction was done on both sides, although collagen sponges were placed only in the sockets of the test sides. Pre-operative (day 1) evaluation included eruption status, pain by Visual Analogue Scale, and mouth opening by a caliper. On day 3, pain assessment was done and repeated on day 7, with mouth opening and empty sockets.</p> Results <p>Thirty-one patients, 80.6% female, were included. The ages ranged from 20 to 42 years. No significant difference in pain scores was found between the two sides on day 1; however, the pain was significantly higher on the control side on days 3 (<i>p</i> = 0.002) and 7 (<i>p</i> = 0.001). The mean mouth opening was minimally larger on the test side on day 7 (<i>p</i> = 0.465). Only 3 cases (9.7%) of empty sockets and food debris on the control side reported pain greater than 5, and they were diagnosed as AO without significant difference (<i>p</i> = 238) between the two sides.</p> Conclusion <p>Intra-alveolar application of collagen sponge following surgical extraction of IL3rdM significantly reduced post-operative pain on days 3 and 7. Moreover, it can minimally decrease the incidence of AO.</p> Clinical relevance <p>Surgical extraction of IL3rdM is a frequent procedure. Alleviating the pain and other complications improves the patient’s quality of life.</p>