Objective The aim of this study was to determine whether a Mediterranean‐style, ketogenic diet mobile health application (app) with breath acetone biofeedback is superior to a calorie‐restricted, low‐fat diet app in promoting weight loss. Methods Participants (n = 155) with overweight/obesity (mean SD: age 41 11 years, BMI = 34 5 kg/m2, 71% female) were randomized to one of the interventions delivered entirely via app. Participants received a wireless scale and were instructed to take daily weight measurements. A third‐party laboratory collected blood samples at baseline and 12 weeks. Results Weight loss at 12 weeks was greater in the ketogenic (−5.6 kg; 95% CI: −6.7 kg to −4.5 kg) compared with the low‐fat group (−2.5 kg; 95% CI: −3.6 kg to −1.4 kg) (between‐group difference: −3.1 kg; 95% CI: −4.6 kg to −1.5 kg; p < 0.001). Weight loss at 24 weeks indicated durability of the effect (between‐group difference: −5.5 kg; 95% CI: −8.3 kg to −2.8 kg; p < 0.001). Secondary/exploratory outcomes of hemoglobin A1c and liver enzymes were improved to a greater extent in the ketogenic diet group (p < 0.01). Conclusions Among adults with overweight/obesity, a ketogenic diet app with breath acetone biofeedback was superior to a calorie‐restricted diet app at promoting weight loss in a real‐world setting.