Background: The adoption of protective behaviors represents a crucial measure to counter the spread of infectious diseases. The development of effective behavior change interventions therefore emerged as public health priority during the COVID-19 pandemic, but randomized controlled trials testing such interventions during the pandemic were scarce. We conducted a Multiphase Optimization Strategy (MOST) to develop, optimize and evaluate a smartphone app, Soapp+, to promote hand hygiene during the COVID-19 pandemic. Purpose: In this paper, we present the results of the evaluation phase of Soapp+ that tested the app’s efficacy in promoting hand hygiene in comparison to an active control group that used a simplified version of the same app. Methods: We conducted a randomized controlled trial from March 2022 to April 2023 involving 193 participants. After baseline, the Soapp+ intervention lasted 32 days, followed by a post-intervention assessment and a 6-month follow-up. The primary outcome was the difference in hand hygiene behavior pre-post, and pre-follow-up. Hand hygiene was assessed with electronic diaries. Group differences were tested intention-to-treat with the Student’s t-test and the non-parametric Wilcoxon Rank Sum test. Results: Pre-registered t-tests didn’t show significant differences between groups. Differently, non-parametric analyses evidenced significant group differences in hand hygiene between pre-post and pre-follow-up in favor of the group using the full version of Soapp+. Conclusions: Soapp+ was developed through a rigorous experimental method during the ongoing COVID-19 pandemic. The randomized controlled trial provided mixed but encouraging evidence for the efficacy of Soapp+ to promote hand hygiene in the context of a pandemic.