Background: Electronic mental (e-mental) health interventions can address mental health needs of different populations. Cultural adaptation of these interventions is crucial to establish a better fit with the cultural group and to achieve better treatment outcomes. Objective: This study aimed to describe the cultural adaptation of the World Health Organization's e-mental health program Step-by-Step for overseas Filipino workers. We used a framework which posits that cultural adaptation should enhance (1) relevance, wherein the cultural group can relate with the content; (2) acceptability, where the cultural group will not find any element offensive; (3) comprehensibility, where the program is understandable; and (4) completeness, wherein the adapted version covers the same concepts and constructs as the original program. We aimed to have English and Filipino and male and female versions. Methods: Overall, 3 experienced Filipino psychologists provided their perspectives on the program and how it might be adapted for overseas Filipino workers. We then adapted the program and obtained feedback from 28 overseas Filipino workers from diverse industries through focus group discussions. We conducted 7 and 9 focus group discussions with male and female participants, respectively. Per discussion, cognitive interviewing was used to probe for relevance, acceptability, comprehensibility, and completeness of illustrations and text. Participant feedback guided iterative program adaptations, which were again shown to participants for validation and improvement. Results: Several issues were raised by participants about the generic version of Step-by-Step. There were elements deemed irrelevant, like unfitting characters, lack of Filipino values, and unsuitable problems and activities. There were unacceptable components that were stigmatizing, political, inappropriate to context or subgroups, and too feminine for male users. Some elements were incomprehensible, unclear, or complicated. To address these issues, we made key adaptations. To enhance relevance, we adapted the narrative to match the experiences of overseas Filipino workers, incorporated Filipino values, and illustrated familiar problems and activities. To increase acceptability, our main characters were changed to wise elders rather than health professionals (reducing mental health and help-seeking stigma), political or unacceptable content was removed, and the program was made suitable for overseas Filipino workers from different sectors. To increase comprehension, we used English and Filipino languages, simplified the text to ease interpretation of abstract terms, and ensured that text and illustrations matched. We also used Taglish (ie, merged English and Filipino) when participants deemed pure Filipino translations sounded odd or incomprehensible. Finally, we retained the core elements and concepts included in the original Step-by-Step program to maintain completeness. Conclusions: This study showed the utility of a 4-point framework that focuses on acceptance, relevance, comprehensibility, and completeness in cultural adaptation. Moreover, we achieved a culturally appropriate adapted version of the Step-by-Step program for overseas Filipino workers. We discuss lessons learned in the process to guide future cultural adaptation projects of e-mental health interventions.