This study investigates the antiproliferative and pro-apoptotic effects of the postbiotics nisin and urolithin B (UB) on lymphoma cells, individually and in combination. Human Burkitt lymphoma (HKB-11) and Hs 313.T cell lines and normal stromal HS-5 cells were treated with nisin, UB, and nine different ratios of their combinations. A 7:3 ratio (nisin 5600 μM + UB 150 μM) demonstrated synergistic anticancer activity with minimal cytotoxicity to normal cells. Flow cytometry confirmed that UB alone was the most potent inducer of apoptosis (p < 0.0001), followed by the 7:3 combination, significantly improving nisin’s apoptotic effect. Reactive oxygen species (ROS) assays demonstrated that nisin triggered concentration-dependent ROS production, whereas UB modulated this effect when combined, thereby reducing oxidative stress. Label-free proteomic analysis revealed distinct expression profiles. Nisin treatment upregulated oxidative stress-related proteins (HBA1, CYC1) and suppressed cell cycle proteins (CDK1, CCNB1), indicating mitotic inhibition. UB altered mitochondrial and epigenetic regulators (CYCS, DNMT1), and the combination therapy significantly downregulated ribosomal proteins (RPS14, RPL11, RPS27) and TP53, suggesting that ribosomal stress mediates antiproliferative effects. Synergy analysis confirmed combination index (CI) values <1 at 4:6 and 7:3 ratios, validating synergistic interactions.