The history of the use of natural compounds as therapeutic agents goes back many centuries. Being the first object of interest in the early days of medicine, natural compounds are still of great relevance, considering the improvement of methods for isolation, chemical transformation, and synthesis. They are also used in oncology, with the advantage of preventing the development of toxicity to normal cells and resistance in tumor cells. One of the promising classes of natural compounds with antitumor activity is lignans. We studied a number of lignans (arctiin, honokiol, matairesinol, pinoresinol, myrislignan, enterodiol, enterolactone) in the breast cancer cell line MCF7 and the subline MCF7/FUL with acquired resistance to antiestrogen fulvestrant. The antiproliferative activity was assessed by the MTT test. Analysis of the level of intracellular proteins was carried out by immunoblotting. Based on the results of the screening, the most active compound was honokiol; it had the lowest IC₅₀ value for both MCF7 and MCF7/FUL cells, 19.7 μM and 9.1 μM respectively. The revealed antiproliferative activity of honokiol against resistant cells prompted us to study its effects on intracellular proteins associated with proliferation and cell death. Honokiol suppressed the expression of Bcl-2 (an inhibitor of apoptosis) and cyclin D1 (a cell cycle regulator) in both cell lines, but this effect was more pronounced in the resistant subline. The decrease of the expression of antiapoptotic and proliferative proteins induced by honokiol is consistent with its antiproliferative effect, which is more pronounced in resistant subline MCF7/FUL.