Pharmacologic management of acute pain should be tailored for each patient, including a review of treatment expectations and a plan for the time course of prescriptions. Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are first-line treatment options for most patients with acute mild to moderate pain. Topical NSAIDs are recommended for non-low back, musculoskeletal injuries. Acetaminophen is well tolerated; however, lower doses should be used in patients with advanced hepatic disease, malnutrition, or severe alcohol use disorder. Nonselective NSAIDs are effective but should be used with caution in patients with a history of gastrointestinal bleeding, cardiovascular disease, or chronic renal disease. Selective cyclooxygenase-2 NSAIDs are a more expensive treatment alternative and are used to avoid the gastrointestinal adverse effects of nonselective NSAIDs. Adjunctive medications may be added as appropriate for specific conditions if the recommended dose and schedule of first-line agents are inadequate (e.g., muscle relaxants may be useful for acute low back pain). For severe or refractory acute pain, treatment can be briefly escalated with the use of medications that work on opioid and monoamine receptors (e.g., tramadol, tapentadol) or with the use of acetaminophen/opioid or NSAID/opioid combinations. The opioid epidemic has increased physician and community awareness of the harms of opioid medications; however, severe acute pain may necessitate short-term use of opioids with attention to minimizing risk, including in patients on medication-assisted therapy for opioid use disorder.