ABSTRACT Perinatal depression and postpartum depression represent a significant burden for those who experience them and are associated with preterm birth, low birth weight, postpartum hospitalization, diminished mother-child relationships, offspring developmental delay, and other important markers of health and well-being. Perinatal depression, in particular, is underidentified and thus undertreated. This study was designed to assess the MMB eHealth program (MomMoodBooster2 [MMB2]), which is targeted toward perinatal depression, with an aim to assess the effectiveness of the smartphone version of this tool. Primary outcomes were targeted toward analyzing the extent to which MMB2 relieved the severity of anxiety and depression symptoms in general (using both perinatal and postpartum tools); secondary outcomes focused on usage trends along with ratings of usability and helpfulness. Participants were recruited from the Perinatal Depression Program (PDP) in the NorthShore University HealthSystem. Eligibility criteria included pregnant women and women less than a year postpartum, age older than 18 years, no active suicidal ideation, access to internet, and English language proficiency. REDCap (Vanderbilt University Nashville, Tenn) was used for onboarding and randomization. Final analyses included 191 patients randomized into 2 groups, one with MMB2 and the PDP protocol and one with only PDP. After program completion, 93% of patients completed an associated posttest. Primary screenings were not significantly different between groups, and baseline characteristics were likewise consistent. Controlling for perinatal status, posttests showed a significant decrease in depression severity, anxiety, stress, and automatic thoughts (P ≤ 0.001), as well as an increase in behavioral activation and self-efficacy. Further analysis showed that the MMB2 group showed greater decreases from baseline to posttest in both stress (P = 0.019) and depression severity (P = 0.003). No other significant effects were found when comparing the 2 groups. Usage of MMB2 varied, but generally showed that patients visited the program shortly after receiving the first invitation and then periodically on multiple distinct days between their first and last visit to their health care provider (mean [SD] visits, 49.4 [30.2] distinct days). Perinatal tools were used by 41% of participants, and 43% used postpartum tools, with 10% using both tools because of being pregnant at initial recruitment but delivering over the course of the study. The program included text messages for the first 12 weeks, and impact of these was not directly assessed. Of ratings provided, 96% rated the program as “somewhat” to “extremely” easy to use, and 83% of participants rated it as “somewhat” to “extremely” helpful. Many participants in both groups reported using other management strategies such as medication, therapy sessions, and physician advice, but use of these interventions did not differ between groups. These results indicate that MMB2 is effective at reducing anxiety and depression severity, as well as improving self-efficacy. Clinically, this eHealth tool may be an appropriate way to subsidize care for women where in-person options are limited or other options are unavailable. It could also be used to augment in-person options for management of depressive symptoms. Further research should focus on larger and more diverse populations, to understand if the findings are generalizable beyond this small population. In addition, the sustainability and adoption strategies should be optimized to allow this program to be as far reaching as possible. More research could also examine long-term follow-up and durability of the effects of this treatment.