Introduction: Diabetic foot ulcer (DFU) is a common complication of diabetes mellitus associated with increased morbidity and mortality and diminished quality of life (QoL). This study aimed to explore the effect of gender differences on QoL and adherence to self-care activities. Methods: In this cross-sectional study, we enrolled 135 male and 135 female patients with DFU. Data was collected using the Short Form Health Survey (SF-36) and a questionnaire that measured self-care activities (Diet, Exercise, Blood Examination, and Foot Check). Data analysis was performed using SPSS version 20. Results: In terms of QoL, male participants had moderate to high levels in the categories of energy/fatigue, emotional well-being, social functioning, and bodily pain, whereas they had low levels in physical functioning, physical role, and emotional role. Female patients had moderate QoL in the categories of energy/fatigue and social functioning, whereas they had low QoL in physical functioning, physical role, emotional role, emotional well-being, and bodily pain. Finally, regarding general health, male participants had moderate QoL and females had moderate to low QoL. Both males and females had low adherence to exercise and high in blood-examinations. For both genders, adherence to exercise had a statistically significant association with all sub-categories of QoL apart from those of role (physical and emotional). Conclusion: It is essential for health care professionals to provide gender-specific approaches in treatment of ulceration.