This study investigated the potential of Prunus mume (P. mume) extract as an anticancer adjuvant by evaluating its direct apoptotic effects on A375P human melanoma cells and its immunomodulatory impact on peripheral blood mononuclear cells (PBMCs). Furthermore, the extract demonstrated additive and chemosensitizing effects when combined with a sub-toxic dose of cisplatin, significantly enhancing the growth inhibition of A375P cells. Selective growth inhibition was confirmed using crystal violet assays, where the 80% ethanol (EtOH) extract exhibited significant dose-dependent inhibition of A375P viability while leaving human adult low-calcium high-temperature keratinocytes (HaCaT) largely unaffected. Apoptotic cell death was characterized by DNA fragmentation and disrupted mitochondrial membrane potential, which decreased to 77.3% of the control as evidenced by JC-1 staining. At the molecular level, quantitative real-time reverse transcription–polymerase chain reaction (RT-qPCR) analysis demonstrated the upregulation of pro-apoptotic markers, including Bax (2.08-fold at 30 h) and Caspase-3 (2.12-fold in 16 h floating cells), alongside significant downregulation of the anti-apoptotic gene Bcl-2 (down to 0.10-fold at 16 h adherent cells). Notably, initiator Caspase-9 expression was suppressed in co-treated cells, suggesting late-stage transcriptional attenuation during sustained drug exposure. The extract suppressed the NF-κB pathway and reduced PD-L1 mRNA levels by 2.63-fold (compared to 3.55-fold with cisplatin alone), suggesting a mechanism to mitigate chemo-induced inflammatory stress and immune dysregulation. Furthermore, while cisplatin induced an excessive inflammatory response in PBMCs, co-treatment with the extract normalized the cytokine profile by modulating IFN-γ (2.21-fold), TNF-α (3.37-fold), and IL-2 (1.60-fold) back toward baseline levels. The attenuation of cytotoxic effectors, Granzyme B (1.16-fold) and Perforin (0.73-fold), along with the costimulatory molecule CD80 (4.44-fold), suggests the modulation of excessive inflammatory activation and attenuation of immune hyper-responsiveness. Finally, biomolecular docking predictions using the Boltz-2 framework (an open-source biomolecular interaction prediction model) demonstrated high-affinity binding between key plum constituents (e.g., chlorogenic acid, citric acid) and target proteins such as Caspase-3, Bcl-2, Nrf2, and Keap1, providing a structural basis for their bioactivity. In conclusion, P. mume extract (PME) serves as a promising multi-target adjuvant that simultaneously triggers cancer cell apoptosis while mitigating cisplatin-induced inflammatory perturbations in immune cells.