Background: Adiponectin is an adipose-derived hormone that plays a role in various metabolic diseases. We previously demonstrated that adiponectin inhibits melanin synthesis through adenosine monophosphate-activated protein kinase (AMPK) activation in melanocytes. However, melanocytes can be affected by neighboring keratinocytes, and the effect of adiponectin on these functional units has not been investigated. Objective: We investigated the effect of adiponectin on melanogenesis in co-cultured models of normal human melanocytes (NHMs), normal human keratinocytes (NHKs), and human dermal fibroblasts (HDFs), and the effect of adiponectin on melanin content in human skin tissues. Methods: Quantitative real-time polymerase chain reaction (qPCR) was performed for tyrosinase and microphthalmia-associated transcription factor (MITF). The degree of phosphorylation of AMPK, cAMP response element binding protein (CREB), and AKT was evaluated by western blot assay, and Fontana-Masson staining was performed on cultured human skin tissues. Results: Adiponectin decreased the melanin content in the co-culture models of NHMs with NHKs, NHMs with HDFs, and NHMs with both NHKs and HDFs. qPCR revealed that both tyrosinase and MITF were decreased after adiponectin treatment in the co-culture system. Following adiponectin treatment, AMPK was activated in all cell groups; however, the phosphorylation of CREB was decreased in HDFs and NHKs. The phosphorylation of AKT was decreased in only NHMs. In the experiment with human skin tissues cultured ex vivo, the densitometric analysis of Fontana-Masson staining revealed that adiponectin treatment reduced the melanin level of ultraviolet-irradiated human skin tissues. Conclusion Adiponectin inhibited melanogenesis in both co-culture models and human skin tissues ex vivo.