<p>This study investigates the synergistic antifibrotic potential of coumarin derivatives Bergapten (BER) and Esculetin (ESC) in idiopathic pulmonary fibrosis (IPF), a progressive lung disease characterized by epithelial-mesenchymal transition and fibrotic remodeling. Current therapies have limited effectiveness, often focusing on single pathways and failing to reverse disease progression. Therefore, synergistic and multi-targeted strategies are required to inhibit key profibrotic signals with minimal toxicity. In this research, an <i>in-silico</i> and <i>in-vitro</i> approach was used to evaluate whether ESC enhances the cytotoxic activity of BER in fibroblast models. <i>In-silico</i> Pharmacokinetic profiling using SwissADME and pkCSM confirmed favorable drug-likeness, low toxicity, and good absorption. Target prediction and Network pharmacology identified 104 common targets, with MTOR and TGF-β1 identified as major regulators within the PI3K/Akt/mTOR signaling pathway. Molecular docking studies indicate strong binding affinities of BER and ESC toward these targets, while molecular dynamics simulations indicate stable MTOR-ligand interactions compared to TGF-β1. MM-GBSA analyses further supported their binding stability, and density functional theory calculations indicated favorable HOMO–LUMO energy gaps correlated with redox reactivity. <i>In-vitro</i> studies using L929 fibroblasts showed that ESC significantly enhanced the cytotoxic efficacy of BER, particularly at fixed ratios of 1:2 and 2:1, as validated by the Chou-Talalay method (combination index &lt; 1 and Dose Response Index &gt; 1). The 1:2 ratio exhibited the strongest synergistic effect, and these results support the potential of BER and ESC as antifibrotic agents for further evaluation in IPF.</p> Graphical abstract <p>Flowchart of network pharmacology-based target identification and <i>In-vitro</i> Chou-Talalay-based dose prediction for Bergapten and Esculetin in idiopathic pulmonary fibrosis</p>