AbstractNine cyclic diarylheptanoids, 1–9, including two new compounds, i.e., 9‐oxoacerogenin A (8) and 9‐O‐β‐D‐glucopyranosylacerogenin K (9), along with three acyclic diarylheptanoids, 10–12, and four phenolic compounds, 13–16, were isolated from a MeOH extract of the bark of Acer nikoense (Aceraceae). Acid hydrolysis of 9 yielded acerogenin K (17) and D‐glucose. Two of the cyclic diarylheptanoids, acerogenin A (1) and (R)‐acerogenin B (5), were converted to their ether and ester derivatives, 18–24 and 27–33, respectively, and to the dehydrated derivatives, 25, 26, 34, and 35. Upon evaluation of compounds 1–16 and 18–35 for their inhibitory activities against melanogenesis in B16 melanoma cells, induced with α‐melanocyte‐stimulating hormone (α‐MSH), eight natural glycosides, i.e., six diarylheptanoid glycosides, 2–4, 6, 9, and 12, and two phenolic glycosides, 15 and 16, exhibited inhibitory activities with 24–61% reduction of melanin content at 100 μM concentration with no or almost no toxicity to the cells (88–106% of cell viability at 100 μM). In addition, when compounds 1–16 and 18–35 were evaluated for cytotoxic activity against human cancer cell lines, two natural acyclic diarylheptanoids, 10 and 11, ten ether and ester derivatives, 18–22 and 27–31, and two dehydrated derivatives, 34 and 35, exhibited potent cytotoxicities against HL60 human leukemia cell line (IC50 8.1–19.3 μM), and five compounds, 10, 11, 20, 29, and 30, against CRL1579 human melanoma cell line (IC50 10.1–18.4 μM).