Xanthones are a class of heterocyclic compounds characterized by a dibenzo-γ-pyrone nucleus. Analysis of their mode of action in cells, namely uncovering alterations in gene expression, is important because these compounds have potential therapeutic applications. Thus, we studied the transcriptional response of the filamentous fungus Neurospora crassa to a group of synthetic (thio)xanthone derivatives with antitumor activity using high throughput RNA sequencing. The induction of ABC transporters in N. crassa, particularly atrb and cdr4, is a common consequence of the treatment with xanthones. In addition, we found a group of genes repressed by all of the tested (thio)xanthone derivatives, that are evocative of genes downregulated during oxidative stress. The transcriptional response of N. crassa treated with an acetophenone isolated from the soil fungus Neosartorya siamensis shares some features with the (thio)xanthone-elicited gene expression profiles. Two of the (thio)xanthone derivatives and the N. siamensis-derived acetophenone inhibited the growth of N. crassa. Our work also provides framework datasets that may orientate future studies on the mechanisms of action of some groups of xanthones.