AbstractAn innovative approach for nano‐liquid chromatography (LC) gradient generation is presented. This system represents an optimized and refined version of a prototype proposed by the authors a few years ago: the current version is characterized by a new configuration that guarantees complete automation and easier operation. The core of the system is an electronically controlled, multiposition valve that hosts six loops, filled with different mobile phase compositions of increasing strength. A conventional flow rate of water is reduced at nano‐scale through a split device to push the content of the on‐line loop into the column. No mixing occurs between solvents inside the loops, due to the low flow rate and the reduced loop diameter. Valve actuation allows the selection of the on‐line loop to obtain the solvent gradient. The evaluation of the system performance takes into account gradient accuracy, precision, delay time, shape (linear, convex, or concave), and organic solvent consumption. Results highlight the reliability and the competitiveness of the system, especially in terms of accuracy and precision. A comparison between the described system and a conventional split‐based one demonstrates that the new approach reduces the solvent consumption by about 40 times, improving green chromatography and cutting laboratory costs.