As a compelling alternative to fossil fuel combustion, air-source heat pumps face challenges in inefficiency, flammability, and pollution when operated at low ambient temperatures. To address the demand for safe, eco-friendly and efficient heating during wintertime, this work is devoted to exploring a novel refrigerant for air-source heat pumps. The zeotropic mixture has the potential to meet all the above demands at appropriate operating parameters, although specific feasible mixtures are still under investigation. In this work, a novel mixture of carbon dioxide and trans-1,1,1,4,4,4-hexafluoro-2-butene is proposed, with the heating performance being parametrically optimized based on a genetic algorithm. Energy analysis indicates a coefficient of performance improvement of up to 15.7 %, and thus an improvement in heating seasonal performance factor of more than 13.5 % for different cities, compared with traditional configurations. Exergy analysis shows that the low irreversibility of throttling is the main contributing factor to the improvement in energy efficiency. Meanwhile, economic and environmental analyses reveal a payback period of less than 7.5 years and an annual cost reduction of up to 14.5 %, as well as a carbon dioxide emission reduction of over 15.7 %. The sensitivity of operating parameters is analyzed, and other advantages of this concept are discussed as well. The results indicate a safe, efficient, environmentally friendly, and cost-effective air-source heat pump. This study contributes to: 1) providing an energy-efficient and environmentally friendly alternative refrigerant for heat pumps; and 2) promoting the sustainable development of low-carbon energy transformation technology.