The invention belongs to the technical field of medicinal chemistry, and specifically relates to a multi-substituted naphthoquinone derivative and its preparation method and application. The structure of the derivative is shown in the general formula (I), wherein, R 1 selected from ethoxy, diphenylmethoxy, linalyl, D-menthol; R 2 selected from thiophene, phenyl, p-bromophenyl, p-methoxyphenyl, 2,4,6-trimethylphenyl; R 3 selected from hydrogen, nitro; R 4 Selected from hydrogen, fluorine, and bromine; the derivative has a novel structure and has a good antitumor effect, especially has a good inhibitory effect on colorectal adenocarcinoma cells, osteosarcoma cells and breast cancer cells. It has great application value and is expected to be prepared as an antitumor drug; at the same time, the preparation method of the polysubstituted naphthoquinone derivative has fewer reaction steps, simple and safe operation, low cost, less waste generation, high atom economy, and high selectivity. Sex, the advantage of high yield.