Conventional meat production has become a force of environmental damage, but global meat consumption is predicted to continue increasing. Therefore, the technology of cultivated meat is undergoing rapid development. The current study explores what factors explain U.S. consumers’ intention to purchase cultivated meat as a sustainable substitute for conventional meat by applying a dual-factor model. A total of 410 completed responses were received from a nationwide survey. Structural equation modeling was conducted to test the model and hypotheses. The results showed that physical health, animal welfare, and food quality significantly encouraged consumer acceptance of cultivated meat as a sustainable substitute for conventional meat. Food technology neophobia significantly inhibits the acceptance of cultivated meat, whereas unnaturalness did not show an impact on cultivated meat acceptance. Furthermore, the acceptance of cultivated meat as a sustainable substitute significantly enhanced consumers’ purchase intention. The findings inform practitioners about promoting cultivated meat in that marketers should emphasize the benefits of cultivated meat with health, animal welfare, food quality, and the environment. While technological language should be used carefully to avoid food technology neophobia, it is also essential to educate consumers on the science of cultivated meat in order for them to understand its benefits to sustainability.