Using three large-scale longitudinal datasets collected from a cohort of university students over the span of 3 years (total N = 2,896 participants; ecological momentary assessments = 129,414), we found that engagement in meaningful social interactions with peers was associated with lower momentary loneliness and greater affective well-being. We also examined the role of four contextual factors (interaction partners, communication channels, places, and co-occurring activities) in explaining the relationships between meaningful social interactions and momentary well-being. Across samples, we found (a) participants reported experiencing greater loneliness and lower affective well-being after engaging in meaningful social interaction via computer-mediated channels (and via direct messaging in particular), compared to face-to-face, and (b) participants reported experiencing lower affective well-being after engaging in meaningful social interactions while dining and studying or working, compared to while resting. Taken together, our findings provide insight into the relationships between meaningful social interactions, momentary well-being, and contextual factors.