Energy efficient healthy buildings design is important in achieving carbon neutrality and occupants’ health, yet not sufficiently explored. This paper aims to optimize a healthy building in Shanghai, China, based on energy consumption, indoor air quality and visual comfort. A four-step optimization method was proposed. Firstly, Latin Hypercube-Soubert sampling method was used to generate 375 design samples and performance data through computer simulation and calculation. Secondly, five different machine learning approaches were applied for prediction model development. Thirdly, the best prediction models were coupled with eleven optimization algorithms to find Pareto solutions. Finally, optimization on different combinations of design parameters were conducted. It was found that the back propagation neural network and Pareto Envelope-based Selection Algorithm II were the best prediction models and optimization algorithm. The average reduction of building energy consumption, visual discomfort, and improper indoor air quality hours were found to be 25.73 %, 46.24 %, and 38.34 %, respectively. The recommended windows to wall ratios of the east, south, west and north walls, absorptance of solar radiation and filter types are in the range of 20%–35 %, 10%–45 %, 10%–30 %, 10%–40 %, 0.7–0.9, and S7-S9, respectively. This study contributes to enrich the case study of healthy buildings, provide a quick design optimization approach and analysis on the importance of each design parameter. Its originality lies in the optimization methodology, comparative analysis of prediction models, optimization algorithms, and combination effects of design parameters. The outcomes can guide the building designers in performing energy efficient design while maximizing indoor air quality and visual comfort.