Abstract Aim Eloralintide (LY3841136) is a potent, long‐acting selective amylin receptor agonist currently under development for the treatment of obesity with once‐weekly subcutaneous dosing. Materials and Methods This 12‐week Phase 1, randomised, placebo‐controlled, participant‐ and investigator‐blinded, multiple ascending dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamic profiles of eloralintide upon once‐weekly subcutaneous dosing without dose escalation in participants with obesity or overweight. Results From 30 March 2022 to 25 January 2024, at three centres in the United States, 100 participants with a mean age of 44 years, 29% female participants, and mean body mass index of 32.6 kg/m 2 , were randomly assigned to receive either eloralintide or placebo in 5 multiple ascending dose cohorts. At Week 12, AUC τ,ss and C max were dose proportional with ratios of dose‐normalised geometric means of 1.1 and 1.0, respectively. The most common treatment‐emergent adverse events (TEAEs) with eloralintide included decreased appetite (19% of participants), headache (12%), fatigue (11%), and COVID‐19 (11%). Gastrointestinal adverse events, including diarrhoea (10% of participants), nausea (8%), and vomiting (4%), were infrequent in those receiving eloralintide. Most TEAEs were mild in severity. No deaths and one serious adverse event (in the 6 mg eloralintide cohort) unrelated to eloralintide occurred. At Week 12 with eloralintide, the least squares mean percent reduction in body weight across the dose groups ranged from 2.6% to 11.3%. Conclusion Eloralintide once weekly was well tolerated with minimal gastrointestinal adverse events and resulted in clinically meaningful weight loss.