Loneliness is a significant risk factor for substance use, however, impacts of treatments on loneliness are relatively unexplored. Living in a rural location is a greater risk factor for loneliness. This study examined data from a quasi-experimental study in rural Appalachia, comparing the effectiveness of Mindfulness-Based Relapse Prevention (MBRP) versus Treatment as Usual (TAU) among adults receiving MOUD in outpatient therapy. Our objective was to determine whether observed reductions in self-reported craving, anxiety, depression, and increased perceived mindfulness would also improve loneliness reports. Eighty participants (n = 35 MBRP; n = 45 TAU) were included in the analysis from a group-based Comprehensive Opioid Addiction Treatment program. Outcomes tracked included craving, anxiety, depression, mindfulness, and loneliness as measured by the Revised UCLA Loneliness Scale (R-UCLA). A linear mixed model ANOVA determined the significance of the treatments on changes in loneliness scores at baseline, 12 weeks, 24 weeks, and 36 weeks post-recruitment. Both groups reported significantly reduced loneliness over the course of the study (F = 16.07, p < 0.01), however there were no significant differences between groups. Loneliness was also significantly positively (p < 0.01) correlated with anxiety (0.66), depression (0.59), and craving (0.38), and significantly (p < 0.01) inversely correlated (−0.52) with mindfulness. Results suggest that participation in MOUD group-based outpatient therapy has the potential to diminish loneliness and associated poor psychological outcomes. Thus, it is possible that a more targeted intervention for loneliness would further diminish loneliness, which is important as loneliness is linked to risk for relapse.