Background Experts in the field of medical education emphasized the need for curricula that improve students’ attitudes toward the underserved. However, some studies have shown that medical education tends to worsen these attitudes in students. We aimed at systematically reviewing the literature assessing the change in medical students’ attitudes toward the underserved and intention to work with the underserved throughout medical education, the sociodemographic and educational factors associated with favorable medical student attitudes toward and/or intention to work with the underserved and the effectiveness of educational interventions to improve medical student attitudes toward and/or intention to work with the underserved. Method We conducted a systematic review on MEDLINE, Scopus, and Web of Science databases. Three investigators independently conducted the electronic search. We assessed the change in medical students attitudes toward the underserved by computing a weighted mean effect size of studies reporting scores from validated scales. The research team performed a meta-analysis for the sociodemographic and educational factors associated with medical students attitudes toward and/or intention to work with the underserved. Results Fifty-five articles met the inclusion criteria, including a total of 109,647 medical students. The average response rate was 73.2%. Most of the studies were performed in the USA (n = 45). We observed a significant decline of medical students attitudes toward the underserved throughout medical education, in both US and non-US studies. A moderate effect size was observed between the first and fourth years (d = 0.51). Higher favorable medical students attitudes toward or intention to work with the underserved were significantly associated with female gender, being from an underserved community or ethnic minority, exposure to the underserved during medical education and intent to practice in primary care. Regarding educational interventions, the effectiveness of experiential community-based learning and curricula dedicated to social accountability showed the most positive outcome. Conclusions Medical students attitudes toward the underserved decline throughout medical education. Educational interventions dedicated to improving the attitudes or intentions of medical students show encouraging but mixed results. The generalizability of our results is impeded by the high number of studies from the global-North included in the review.