Hydrated magnesium silicate (or “talc” particles) is a sclerosis agent commonly used in the management of malignant pleural effusions (MPE), a common symptom of metastatic diseases including lung cancers. However, the direct effects of talc particles to lung carcinoma cells, which can be found in the MPE fluids from lung cancer patients, are not fully understood. Here, we report a study of the signaling pathways that can modulate the cell death and interleukin (IL)-6 secretion induced by talc particles in human lung carcinoma cells. We found that talc-sensitive cells have higher mRNA and protein expression of phosphoinositide 3-kinase (PI3K) catalytic subunits α and β. Further experiments confirmed that modulation (inhibition or activation) of the PI3K pathway reduces or enhances cellular sensitivity to talc particles, respectively, independent of the inflammasome. By knocking down specific PI3K isoforms, we also confirmed that both PI3Kα and β mediate the observed talc effects. Our results suggest a novel role of the PI3K pathway in talc-induced cell death and IL-6 secretion in lung carcinoma cells. These cellular events are known to drive fibrosis, and thus further studies of the PI3K pathway may provide a better understanding of the mechanisms of talc sclerosis in the malignant pleural space.