Background: Substance use disorder is one of the severe public health problems worldwide. Inequitable resources, discrimination, and physical distances limit patients’ access to medical help. Automated conversational agents have the potential to provide in-home and remote therapy. However, automatic dialogue agents mostly use text and other methods to interact, which affects the interaction experience, treatment immersion, and clinical efficacy. Objective: The aim of this paper is to describe the design and development of Echo-APP, a tablet-based app with the function of a virtual digital psychotherapist, and to conduct a pilot study to explore the feasibility and preliminary efficacy results of Echo-APP for patients with methamphetamine use disorder. Methods: Echo-APP is an assessment and rehabilitation program developed for substance use disorder (SUD) by a team of clinicians, psychotherapists, and computer experts. The program is available for Android tablets. In terms of assessment, the focus is on the core characteristics of SUD, such as mood, impulsivity, treatment motivation, and craving level. In terms of treatment, Echo-APP provides 10 treatment units, involving awareness of addiction, motivation enhancement, emotion regulation, meditation, etc. A total of 47 patients with methamphetamine dependence were eventually enrolled in the pilot study to receive a single session of the Echo-APP–based motivational enhancement treatment. The outcomes were assessed before and after the patients’ treatment, including treatment motivation, craving levels, self-perception on the importance of drug abstinence, and their confidence in stopping the drug use. Results: In the pilot study, scores on the Stages of Change Readiness and Treatment Eagerness Scale and the questionnaire on motivation for abstaining from drugs significantly increased after the Echo-APP–based treatment (P<.001, Cohen d=–0.60), while craving was reduced (P=.01, Cohen d=0.38). Patients’ baseline Generalized Anxiety Disorder-7 assessment score (β=3.57; P<.001; 95% CI 0.80, 2.89) and Barratt Impulsiveness Scale (BIS)–motor impulsiveness score (β=–2.10; P=.04; 95% CI –0.94, –0.02) were predictive of changes in the patients’ treatment motivation during treatment. Moreover, patients’ baseline Generalized Anxiety Disorder-7 assessment score (β=–1.607; P=.03; 95% CI –3.08, –0.14), BIS—attentional impulsivity score (β=–2.43; P=.004; 95% CI –4.03, –0.83), and BIS—nonplanning impulsivity score (β=2.54; P=.002; 95% CI 0.98, 4.10) were predictive of changes in craving scores during treatment. Conclusions: Echo-APP is a practical, accepted, and promising virtual digital psychotherapist program for patients with methamphetamine dependence. The preliminary findings lay a good foundation for further optimization of the program and the promotion of large-scale randomized controlled clinical studies for SUD.