Purpose: Lymphopenia is a common adverse event following radiotherapy, but its prognostic relevance following comprehensive involved-site radiation (ISRT) for oligometastatic disease is unknown. We evaluated lymphocyte kinetics after ISRT for oligometastases and tested whether treatment-related lymphopenia was associated with overall survival (OS) and modified progression-free survival (mPFS). Patients and Methods: We performed a single-institution registry study of consecutive patients with 1 to 5 distant metastases treated with comprehensive ISRT by a single radiation oncologist from 2014 to 2023. Systemic therapy was administered at clinician discretion. Absolute lymphocyte count (ALC) was collected at baseline, during radiation and at 1, 3 and 12 months after radiotherapy. Lymphopenia was graded using CTCAE v5.0 (grade 1, ALC < 1000 cells/µL; grade ≥ 3, ALC < 500 cells/µL). OS and mPFS (defined as death or metastatic progression not salvageable with further local therapy) were estimated by the Kaplan–Meier method. Associations were evaluated using univariable and multivariable Cox proportional hazards models. Results: Among 177 patients, the 5-year OS was 39.6% and the median OS was 42.8 months. Median ALC declined from 1400 cells/µL at baseline to 800 cells/µL during radiotherapy (p < 0.01) and 700 cells/µL at a median of 0.7 months after radiation (p < 0.01). Partial recovery was observed at 1000 cells/µL at 3 months (p < 0.001) and 1000 cells/µL at 1 year (p < 0.01). Baseline ALC <1000 cells/µL was associated with worse OS on univariable analysis (p = 0.04) but not on multivariable analysis. Although 27% developed grade ≥ 3 lymphopenia within 3 months of radiation, the 5-year overall survival was 41.4% without lymphopenia versus 31.9% with lymphopenia (p = 0.60). On multivariable analysis, ECOG performance status (HR 1.9, p < 0.01), age (HR 1.04, p < 0.01), albumin (HR 0.6, p = 0.03), and pre-radiation chemotherapy (HR 3.1, p < 0.01) independently predicted overall survival. Conclusions: Comprehensive ISRT for oligometastatic disease was associated with a sustained decrease in median ALC. Treatment-related lymphopenia was not independently associated with OS in this heterogeneous cohort. The disease control benefit of metastasis-directed therapy may outweigh potential detrimental immunologic effects of radiation-induced lymphopenia.