Background Digital behavioral weight loss programs are scalable and effective, and they provide an opportunity to personalize intervention components. However, more research is needed to test the acceptability and efficacy of personalized digital behavioral weight loss interventions. Objective In a 6-month single-arm trial, we examined weight loss, acceptability, and secondary outcomes of a digital commercial weight loss program (WeightWatchers). This digital program included a personalized weight loss program based on sex, age, height, weight, and personal food preferences, as well as synchronous (eg, virtual workshops and individual weekly check-ins) and asynchronous (eg, mobile app and virtual group) elements. In addition to a personalized daily and weekly PersonalPoints target, the program provided users with personalized lists of ≥300 ZeroPoint foods, which are foods that do not need to be weighed, measured, or tracked. Methods We conducted a pre-post evaluation of this 6-month, digitally delivered, and personalized WeightWatchers weight management program on weight loss at 3 and 6 months in adults with overweight and obesity. The secondary outcomes included participation, satisfaction, fruit and vegetable intake, physical activity, sleep quality, hunger, food cravings, quality of life, self-compassion, well-being, and behavioral automaticity. Results Of the 153 participants, 107 (69.9%) were female, and 65 (42.5%) identified as being from a minoritized racial or ethnic group. Participants’ mean age was 41.09 (SD 13.78) years, and their mean BMI was 31.8 (SD 5.0) kg/m2. Participants had an average weight change of −4.25% (SD 3.93%) from baseline to 3 months and −5.05% (SD 5.59%) from baseline to 6 months. At 6 months, the percentages of participants who experienced ≥3%, ≥5%, and ≥10% weight loss were 63.4% (97/153), 51% (78/153), and 14.4% (22/153), respectively. The mean percentage of weeks in which participants engaged in ≥1 aspects of the program was 87.53% (SD 23.40%) at 3 months and 77.67% (SD 28.69%) at 6 months. Retention was high (132/153, 86.3%), and more than two-thirds (94/140, 67.1%) of the participants reported that the program helped them lose weight. Significant improvements were observed in fruit and vegetable intake, physical activity, sleep quality, hunger, food cravings, quality of life, and well-being (all P values <.01). Conclusions This personalized, digital, and scalable behavioral weight management program resulted in clinically significant weight loss in half (78/153, 51%) of the participants as well as improvements in behavioral and psychosocial outcomes. Future research should compare personalized digital weight loss programs with generic programs on weight loss, participation, and acceptability.