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Coumarin derivatives are characterised by a wide range of therapeutic applications, including anti-tumour activity. Using in silico and in vitro approaches, we evaluated the possible antitumor effects of four 3-cinnamoyl-4-hydroxycoumarin derivatives in diffuse large B-cell lymphoma (DLBCL) cells.. Also, molecular properties and several ADME parameters were our subjects of investigation. The results of an in silico molecular docking analysis show that coumarin compounds have a strong affinity for binding to Akt, NF-κB and Mcl-1 protein targets, which are important for controlling the growth, differentiation and survival of DLBCL cells. Analysed molecular and ADME properties show that compounds satisfy Lipinski’s rule of five. The WST-8 test showed that coumarin derivatives with bromine substituents had a strong cytotoxic effect on HBL-1 cells, which are a type of more aggressive activated B-cell (ABC) DLBCL. However, treatment of DHL-4 germinal centre B-cell (GCB) DLBCL cells with the same substanceshowed no inhibitory activity, suggesting diverse mechanism of action among two distinct DLBCL models. Western blot analysis indicated stimulatory activity of compound 2, with increased Akt phosphorylation levels in both types of cells. These results represent an insight into the activation of the compensatory Akt mechanisms in DLBCL cells. This could represent a key step in combinatorial treatment approaches in order to avoid drug resistance and achieve greater therapeutic efficacy in DLBCL cells.