Lipid nanoparticles (LNPs), containing ionizable cationic lipids, have attracted widespread interest in recent years, particularly following their use as mRNA delivery systems for COVID-19 vaccines. Here, we report on the combinatorial synthesis of galloyl amidoamine-based ionizable lipids. Starting from methyl gallate, three alkyl tails were substituted onto the aromatic ring, and the carboxylic acid was transformed into an ionizable tertiary amine headgroup. Optimization of the synthetic protocol resulted in a scalable, chromatography-free procedure requiring as few as two transformation steps and yielding a library of 43 different lipids in high yield (>88%). By varying the ionizable amine headgroup and the length, saturation, and branching of the alkyl tails, we found that the length of the lipid tail significantly impacted solubility and mRNA encapsulation efficiency. Trialkyl lipids comprising unsaturated heptyl and octyl tails enabled the formulation of sub-150 nm LNPs with encapsulation efficiencies exceeding 85%. Benchmarking experiments against a commercial MC3 LNP formulation identified four lipids that enabled potent mRNA transfection in vitro. Moreover, in vivo studies in mice with selected LNP formulations indicated that three lipids performed on par with MC3 in terms of luciferase reporter-protein expression in the liver and spleen after intravenous administration. Additionally, these lipids did not show any toxicity in the spleen and liver. These results clearly highlight the translational potential of trialkyl galloyl amidoamine lipids and more particularly for mRNA-based therapies.