Grammatophyllum speciosum is a traditional plant with beneficial functionalities for health. G. speciosum extracts can inhibit collagenase and nitric oxide without cellular toxicity in keratinocytes. The extracts have shown potential for use and formulation as cosmeceutical ingredients. However, the molecular mechanisms underlying these activities remain unknown. In this dataset, we used a proteomics approach to clarify the proteins that participate in the response of RAW264.7 macrophage cells to G. speciosum extracts. Cells were divided into two experimental groups, i.e., the control and treatment groups. In turn, the treatment group included two subgroups that were treated with 20 and 100 g/mL of the extracts, respectively. The experiments were conducted using two biological replicates. The dataset was obtained from label-free proteomics using high-resolution LC-MS/MS with four technical replicates. The quality control (QC) of the proteomics dataset was carried out using chromatography at the MS1 and MS2 levels, peptide mass deviation, peptide mass cleavage, sequence length, and total peptide intensity.