Objective The aim of this research was to assess university students’ health-related quality of life whether they use some contraceptive method or not. Methods This research is a cross-sectional study. Female participants who studied a degree in health at the University of Seville (Spain) were recruited. Respondents completed a demographic questionnaire and health-related quality of life was measured with validated instrument SEC-QoL (Sociedad Española de Contracepción- Quality of Life) in Spanish that measured five dimensions: sexual, social, breast, menstrual and psychosocial. Results A total of 992 women aged 21.37 (3.6) years old participated in this study. Women who used a contraceptive method reached higher scores at the SEC-QoL questionnaire 47.09 (17.04) and 46.91 (18.73) than those that didn’t. Likewise, women who chose a hormonal method showed a better overall health-related quality of life, compared to those who used a non-hormonal method. Participants who used hormonal contraceptives obtained higher scores in all health-related quality of life domains (social, menstrual, breast and sexual), except psychological domain when compared to those who used a non hormonal method or none. Furthermore, a moderated mediation model showed that the effect of the current contraceptive method on health-related quality of life was partially explained by the moderated mediation of the time using this method, the reason for using it and the existence of a partner. Conclusion The usage of hormonal contraceptives increases health-related quality of life in young women. Several variables regarding the experience with contraceptive methods should be considered in order to examine the effect on health-related quality of life in undergraduate women.