Prescription opioids for noncancer pain in the United Kingdom have increased over the past 2 decades, alongside associated harms. Policies addressing opioid prescribing must be tailored to individual patient needs with specific disease systems. The aim of this study was to evaluate clinical conditions associated with new opioid initiation in noncancer pain using nationally representative UK data. Primary care electronic health records from January 1, 2006, to September 31, 2021, were used from the Clinical Research Practice Datalink to identify incident opioid prescriptions. Patient histories were reviewed using code lists for opioid-related conditions with a 5-year look-back for chronic conditions and a 1-year look-back for surgical indications before opioid initiation. In total, 3,030,077 new opioid use episodes in 2,027,402 patients were identified, with 61% being women, 77% aged 45 years and older, and 48% from the highest deprivation quintile. Ten systems associated with opioid initiation were identified, which were not mutually exclusive, as patients could have opioids prescribed for multiple indications. The most common were musculoskeletal (80.8%), respiratory (57.6%), infections (30.4%), trauma/injury (20.4%), neurology (19.9%), and postsurgical indications (5.5%). Osteoarthritis (60.7%) and low back pain (41.0%) were the most frequent musculoskeletal conditions. Orthopedic surgeries accounted for 41.2% of all postsurgical indications. This is the first study in the United Kingdom evaluating large-scale national data to assess indications associated with opioid initiation. Nearly 3 quarters of new opioid prescriptions for noncancer pain were in patients with musculoskeletal conditions, often for conditions with limited evidence for opioid efficacy. These findings could inform targeted interventions and future policies to support nonpharmacological interventions in the most common conditions where opioid harms outweigh benefits.