Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the (LP-cells) tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B cell and peripheral T cell lymphomas exhibit nuclear expression of the Polo-Like Kinase 1 (PLK1) protein, stabilizing c-MYC and associated with worse clinical outcomes. We demonstrate frequent expression of PLK1 in the LP-cells in NLPHL cases (100%, n = 76). In contrast, less than 5% of classical Hodgkin lymphoma cases (n = 70) show PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promotes cell proliferation and increased c-MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in NLPHL patients. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP-cells. The results showed that LP-cells with PLK1(high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. In addition, the findings suggest that an active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.