Our objective was to assess longitudinal health-related quality of life (HRQoL) in patients treated with radiotherapy for gynecologic malignancy and assess the relationship of psychosocial encounters on HRQoL. Methods: Women with gynecologic malignancy were prospectively enrolled and HRQoL assessed before, during, and after radiotherapy treatment using validated measures. Treatment and demographic information were reviewed. Mixed-effects models were used to assess changes in quality of life (QoL) over time and association of psychologist and social worker encounters with overall QoL as well as subdomains of QoL. Results: Fifty-two women were enrolled and 41 completed at least one assessment. Fatigue (p = 0.008), nausea (p = 0.001), feeling ill (p = 0.007), and being bothered by side effects (p < 0.001) worsened on treatment with subsequent improvement. By follow-up, patients reported increased functional well-being (FWB) with significant decrease in worry (p = 0.003), increase in enjoyment of things usually done for fun (p = 0.003) and increase in contentment (p = 0.047). Twenty-three patients had at least one interaction with a social worker or psychologist during treatment. Each additional interaction was associated with a 2.12 increase in FWB score from before to after treatment (p = 0.002), and 1.74 increase from on to after treatment (p = 0.011). Additional interactions were not significantly associated with changes in overall FACT score (p = 0.056) or SWB (p = 0.305). Conclusions: Patient-reported HRQoL significantly worsened during radiotherapy treatment with subsequent improvement, affirming transiency of treatment-induced toxicities. Our preliminary study suggests that clinically recommended psychological and social work interventions have potential value with respect to improving patient QoL during radiotherapy. Larger studies are needed to validate our findings.