Treatment of acromegaly is multimodal for many patients, and medical treatments include somatostatin receptor ligands (SRLs), dopamine agonists (DAs), and growth hormone receptor antagonists (GHRAs). However, recent real-world evidence on treatment patterns for patients with acromegaly is limited. This study evaluated medication usage, treatment changes, adherence, persistence, comorbidities, and healthcare resource utilization, using de-identified data from MarketScan®, a US claims database. Eligible patients (n = 882) were those receiving monotherapy or combination therapy for ≥90 days without treatment gaps. Mean age at diagnosis was 48.6 years; 50.1% of patients were female. Over half (59.4%) had one line of treatment (LOT); 23.1% had two LOTs; 17.5% had at least three LOTs. Most patients (94.6%) initiated treatment with monotherapies. The most common first-line monotherapy treatments were cabergoline (DA, 36.8%), octreotide long-acting release (first-generation SRL, 29.5%), and lanreotide depot (first-generation SRL, 22.5%). Adherence for first-line treatments (proportion of days covered), was higher for first-generation SRLs (lanreotide depot: 0.8), compared with DAs (0.7). Treatment persistence (time between the first treatment record and a change in LOT/censoring) in LOT 1 was higher for GHRAs (24.8 months) and first-generation SRLs (20.0 months), compared with DAs (14.4 months). Female patients and those diagnosed at a younger age were more likely to have shorter treatment persistence. The most prevalent comorbidities were hyperlipidemia, essential hypertension, and sleep apnea. Patients with more comorbidities had more healthcare visits during the first year after diagnosis, suggesting increased disease burden. Real-world evidence on treatment patterns provides insights into recommendations for individualized therapy.