BACKGROUND: Patients with pulpal and periapical conditions often seek treatment for pain, intraoral swelling, or both. Even when definitive, conservative dental treatment (DCDT) is an option, antibiotics are often prescribed. The purpose of this review was to summarize available evidence regarding the effect of antibiotics, either alone or as adjuncts to DCDT, to treat immunocompetent adults with pulpal and periapical conditions, as well as additional population-level harms associated with antibiotic use. TYPE OF STUDIES REVIEWED: The authors updated 2 preexisting systematic reviews to identify newly published randomized controlled trials. They also searched for systematic reviews to inform additional harm outcomes. They conducted searches in MEDLINE, Embase, the Cochrane Library, and the Cumulative Index to Nursing and Allied Health Literature. Pairs of reviewers independently conducted study selection, data extraction, and assessment of risk of bias and certainty in the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: The authors found no new trials via the update of the preexisting reviews. Ultimately, 3 trials and 8 additional reports proved eligible for this review. Trial estimates for all outcomes suggested both a benefit and harm over 7 days (very low to low certainty evidence). The magnitude of additional harms related to antibiotic use for any condition were potentially large (very low to moderate certainty evidence). CONCLUSIONS AND PRACTICAL IMPLICATIONS: Evidence for antibiotics, either alone or as adjuncts to DCDT, showed both a benefit and a harm for outcomes of pain and intraoral swelling and a large potential magnitude of effect in regard to additional harm outcomes. The impact of dental antibiotic prescribing requires further research.