The subcellular localization of proteins can be highly dynamic and regulated by post-translational modifications. Farnesylation is a lipid modification that enables anchoring of proteins to cellular membranes, and thus, spatially resolved signaling and activity. Due to the importance of farnesylation for cellular functions, farnesyltransferase inhibitors (FTIs) including tipifarnib were developed and are being tested in oncology clinical trials. The current lack of knowledge on the functional impact of FTIs on hundreds of farnesylation substrates limits response prediction and their use in cancer precision medicine. Here, we report a global functional proteomics investigation of the impact of tipifarnib in multiple lung cancer cell lines. This dataset includes proteome-wide analysis of the effects of tipifarnib at 6, 12, 24, 48 h timepoints. The data covers experiments in five lung cancer cell lines (NCI-H727, NCI-H1568, NCI-H1975, NCI-H2009 and NCI-H1944).