Objective To understand the current situation and main influencing factors of career decision-making difficulties of higher vocational medical students, and put forward improvement countermeasures. Methods The method of stratified cluster sampling was adopted, with 740 full-time medical students from a vocational college in Guangzhou being investigated. Results The average score of career decision-making difficulty of medical students surveyed in higher vocational colleges was (3.55±0.647), in which the average score of the career planning exploration was the lowest (3.42±0.797), and the average scores of other dimensions from low to high were career goal exploration (3.49±0.766), career information exploration (3.58±0.678) and career self-exploration (3.69±0.659). The results of one-way analysis of variance (ANOVA) showed that there were significant differences in the scores of career decision-making difficulties of medical students in higher vocational colleges among different majors, the major being the first choice or not, and different living places (P<0.05). The results of multiple stepwise regression analysis showed that family location, school guidance courses for career planning, part-time or trainee experience, school activities (employment guidance lectures, career planning competitions, etc.), being optimistic about the employment prospects of their majors, schools providing sufficient employment information, and having participated in innovation and entrepreneurship competitions were predictors of difficulties in career decision-making for medical students (P<0.05). Conclusions The difficulty of career decision-making of medical students in higher vocational colleges was in the middle level. Schools can establish a systematic evaluation and intervention system aiming at career decision-making difficulties by carrying out targeted career guidance, and build practice and employment service platform to improve the career decision-making difficulties of medical students in higher vocational colleges, and to provide strong support and security for students. The government can enhance policy guidance for medical students in higher vocational colleges to apply for primary hospital.