Objective To study stress changes in forefoot intermetatarsal region when wearing high-heeled shoes, so as to provide references for quantitative analysis on inducement mechanism of intermetatarsal neuroma and corresponding treatment strategy. Methods Based on the validated foot-ankle-shoe finite element platform, changes of stress levels and tendency in intermetatarsal region were analyzed for both in balanced standing when wearing 0-3 inch (0, 2.54, 5.08, 7.62 cm) high-heeled shoes and walking when wearing 5.08 cm high-heeled shoes in a gait cycle. Results With the increase of heel height, the stresses in intermetatarsal region were significantly increased, and the stress in the third web space of toes when wearing 7.62 cm high-heeled shoes reached 312% of that when wearing flat shoes (0 cm high-heeled shoes). When walking with 5.08 cm high-heeled shoes, the third web space of toes at push-off instance had the largest stress, reaching 90 kPa, which agreed with the most commonly pathogenic site of intermetatarsal neuroma in clinic. Conclusions Wearing high-heeled shoes can obviously increase the stress in intermetatarsal region. Squeezing by upper extrusion of shoes can result in the largest stresses in the third web space of toes region, which is most likely to cause the development of intermetatarsal neuroma.