The fourth industrial revolution has attracted much academic attention in these past few years. However, research on systematic and extensive factors affecting adoption of Industry 4.0 by SMEs in developing countries, especially in Vietnam, has been unavailable. This study aims to explore the impact of factors that influence the actual adoption of Industry 4.0 by SMEs in Ho Chi Minh City. Mixed-method research was utilized in this study including in-depth interviews of 12 participants and quantitative research of 396 respondents who are representative of SMEs by both online and via paper surveys. The SPSS and SmartPLS 3 software were employed to help analyze the collected data. The results indicate that perceived development of the human resource, perceived on-time, perceived saving cost, perceived improve product quality, perceived saving time, perceived ease-of-use, business resources, and conditions of the business environment, perceived usefulness, perceived enhanced customer relationship, and adoption intention, all have a positive significant effect on actual adoption of Industry 4.0. The results seem to suggest that managerial efforts aimed at increasing the factors’ perceptions of adoption of Industry 4.0 and personal relevance of the technology will contribute to implementation success, where success is defined as effectual usage of the Industry 4.0.