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Eight hydroxyl groups in (−)-epigallocatechin-3-gallate (EGCG) make it difficult to access the hydrophobic domain of bacterial cell membranes and display strong antibacterial activity at physiologically attainable concentrations. Herein, we strategically modified EGCG into an amphiphilic molecule that can surpass its limitations and transform it into a potent antibacterial agent. Seven EGCG alkyl ether derivatives (4″-Cn EGCG, n = 6, 8, 10, 12, 14, 16, and 18) have been designed, synthesized and assessed for their antibacterial efficacy and mode of action. 4″-C14 EGCG and 4″-C16 EGCG were found to be the most effective antibacterial compounds exhibiting >99% inhibition against Escherichia coli and Bacillus subtilis in the colony numbers at a concentration of as low as 1 μg/mL. They were able to induce intracellular ROS generation and disrupt the cell membrane integrity. Further, enhanced water solubility and antibacterial activity were achieved by synthesizing silver nanoparticles (AgNPs) of 4″-C14 EGCG and 4″-C16 EGCG. The AgNPs were characterized by UV–vis, FT-IR, TEM, and DLS. Compared to EGCG, 4″-C14 EGCG AgNPs exhibited a large reduction in the minimum inhibitory concentration (MIC) with significantly improved water-solubility. Notably, it could eliminate drug-resistant strains such as methicillin-resistant Staphylococcus aureus (>99% at 100 μg/mL), Acinetobacter baumannii (>99% at 10 μg/mL) and Pseudomonas aeruginosa (>99% at 50 μg/mL), indicating broad-spectrum antibacterial activity and high potential to combat antimicrobial resistance. Furthermore, 4″-C14 EGCG, 4″-C16 EGCG and their AgNPs showed strong inhibition of the biofilm formed by Escherichia coli and Bacillus subtilis. The MTT assay on 3T3-L1 mouse fibroblast cells revealed no significant cytotoxicity for 4″-C14 EGCG, 4″-C16 EGCG or their AgNPs up to 150 μg/mL, indicating their selectivity toward bacterial cells. Taken together, this work demonstrates the rational development of amphiphilic EGCG derivatives and their AgNPs that exhibit broad-spectrum antibacterial and antibiofilm activity via multimodal mechanisms. [ABSTRACT FROM AUTHOR]