Humans function based on secure social connections. Loneliness is an important factor that puts individuals at higher risks for poor well-being but explicating potential mediating and moderating factors that may link loneliness to poor well-being has been limited. Based on Hawkley and Cacioppo’s model of loneliness, this study tested whether loneliness is associated with a sense of meaning and purpose in life and explored possible mediating (self-compassion) and moderating (interpersonal mindfulness) effects of this association. A total of 410 university students completed measures of loneliness, self-compassion, meaning in life, interpersonal mindfulness, and trait mindfulness. A moderated mediation model result found that loneliness interferes with showing a healthy attitude toward oneself, linked to a low sense of meaning in life. This effect was exacerbated for those who are less interpersonally mindful. Findings suggest that loneliness stemming essentially from an interpersonal experience gets extended to creating unkind self-attitudes, which then is linked to meaning in life. Moreover, being judgmental and reactive during interpersonal interactions exacerbates this association.