The Disconnection and rejection schema and difficulties in emotion regulation are associated with Non-Suicidal Self-Injury (NSSI). This study examined whether trait mindfulness moderates the association between disconnection and rejection schema, difficulties in emotion regulation and NSSI. Past research has shown mindfulness and self-compassion to be positively related. However, little is known about their interrelationship and the NSSI. We hypothesized that mindfulness would attenuate NSSI, and that the level of self-compassion would modulate this effect. A convenience sample of 454 college student (40.1% male, 59.9% female) aged 19 to 29 years (M = 22.9, SD = 2.2) completed an online questionnaire that disconnection and rejection schema, NSSI, difficulties in emotion regulation, mindfulness, and self-compassion. When mindfulness and self-compassion were in harmony, NSSI decreased significantly. Self-compassion was found to reduce NSSI in participants who developed mindfulness, while it tended to worsen NSSI in participants unfamiliar with mindfulness. The results from this sample highlight the positive interconnections between mindfulness and self-compassion can be leveraged to alleviate the risk factors of NSSI in college students. To maximize the synergistic effects of these two approaches, it is recommended to prioritize mindfulness interventions.