Background The urban heat island effect has a significant negative impact on human health. Urban green space can effectively improve the urban thermal environment while enhancing human thermal comfort. Objective To investigate the effects of vegetation configuration structure on temperature and humidity and on human thermal comfort, with a view to providing reference for the landscape planning of urban reserve, preventing and reducing the impact of urban heat island effect on the health of urban residents. Methods The study was carried out on a typical clear and cloudless summer day without extreme weather in a university reserve area in Hefei. The numerical simulation accuracy of ENVI-met software was verified by measured data. Based on the quantitative definition of vegetation configuration structure scheme from vertical and horizontal perspectives, nine simulation scenarios were established based on three aspects including vegetation configuration type (grass, shrub + grass, tree + grass, tree + shrub + grass), planting layout (column planting, uniform spot planting), and planting density [the aspect ratio of trees (ART) between plants was 0.75, 1.13, 1.50, and 2.25, respectively] to quantitatively evaluate the cooling and humidifying effects and human thermal comfort [physiological equivalent temperature (PET)] of the vegetation configurations. Results The change trends of the cooling and humidifying effects of all the simulated scenarios were consistent, basically first increasing and then decreasing. Among all the simulated scenarios, the cooling and humidifying effects of scenario 8 (tree + grass, ART=2.25, uniform spot planting) were the best, with the greatest cooling of 1.36 ℃ and humidification of 6.29% in comparison to the worst scenario 1 in the reserve area. The human thermal comfort of scenario 9 (tree + shrub + grass, ART=2.25, uniform spot planting) was the best, with the PET of 35.37 ℃. The order of improvement effect of different vegetation configurations on thermal comfort from strong to weak was tree + shrub + grass structure (scenario 9) > tree + grass structure (scenario 8) > shrub + grass structure (scenario 2) > grass structure (scenario 1). At 15:00, the PET value of tree + shrub + grass structure (scenario 9) decreased by 7.44 ℃ in comparison to that of grass structure (scenario 1). The higher the planting density among trees, the higher the difference in temperature and relative humidity between the simulated and the original scenarios. In case of holding the same amount of greenery, uniform spot planting showed better human comfort when the vegetation was planted sparsely, but the difference between the PET value of scenario 3 (tree + grass, ART=0.75, uniform spot planting) and scenario 5 (tree + grass, ART=1.5, column planting) was only 0.15 ℃; when the vegetation was planted densely, column planting was more favorable to wind circulation and more effective in reducing the temperature of the site, with a lower PET value of 0.87 ℃ for scenario 7 (tree + grass, ART=2.25, column planting) than for scenario 4 (tree + grass, ART=1.13, uniform spot planting). Conclusion Urban green space has obvious cooling and humidifying effects in summer. The human comfort of tree + shrub + grass structure with uniform spot planting is optimal, and the cooling and humidifying effects of tree + grass structure with uniform spot planting are the most obvious. The optimization of vegetation configuration structure is crucial for reducing urban heat island, improving human thermal comfort, and promoting residents’ health.