Readily accessible nonpharmacological interventions that can assist in opioid dose reduction while managing pain is a priority for adults receiving long-term opioid therapy (LOT). Few large-scale evaluations of online pain self-management programs exist that capture effects on reducing morphine equivalent dose (MED) simultaneously with pain outcomes. An open-label, intent-to-treat, randomized clinical trial recruited adults (n = 402) with mixed chronic pain conditions from primary care and pain clinics of 2 U.S. academic healthcare systems. All participants received LOT-prescriber-provided treatment of MED ≥ 20 mg while receiving either E-health (a 4-month subscription to the online Goalistics Chronic Pain Management Program), or treatment as usual (TAU). Among 402 participants (279 women [69.4%]; mean [SD] age, 56.7 [11.0] years), 200 were randomized to E-health and 202 to TAU. Of 196 E-heath participants, 105 (53.6%) achieved a ≥15% reduction in daily MED compared with 85 (42.3%) of 201 TAU participants (odds ratio, 1.6 [95% CI, 1.1-2.3]; P = 0.02); number-needed-to-treat was 8.9 (95% CI, 4.8, 66.0). Of 166 E-health participants, 24 (14.5%) achieved a ≥2 point decrease in pain intensity vs 13 (6.8%) of 192 TAU participants (odds ratio, 2.4 [95% CI, 1.2-4.9]; P = 0.02). Benefits were also observed in pain knowledge, pain self-efficacy, and pain coping. The findings suggest that for adults on LOT for chronic pain, use of E-health, compared with TAU, significantly increased participants' likelihood of clinically meaningful decreases in MED and pain. This low-burden online intervention could assist adults on LOT in reducing daily opioid use while self-managing pain symptom burdens.