Background: Medicinal fern species represent a potentially important source for both food and medicinal applications. Previously, two underutilized tropical fern species (Blechnum orientale and Phymatopteris triloba) were reported with cytotoxic activities against selected cancer cell lines. However, the exact mechanism remains elusive. Objective: In this paper, we reported the identification of six differentially expressed proteins isolated from cancer cells, following exposure to the cytotoxic fern extracts. Materials and Methods: The identities of these cancer proteins were determined by matrix-assisted laser desorption ionization time-of-flight protein sequencing. Results: The cancer proteins were identified as follows: elongation factor 1-γ, glyceraldehydes-3-phosphate dehydrogenase, heat shock protein 90-β, heterogeneous nuclear ribonucleoprotein-A2/B1, truncated nucleolar phosphoprotein B23, and tubulin-β chain. To the best of our knowledge, this paper represents thefirst time these cancer proteins are being reported, following exposure to the aforementioned cytotoxic fern extracts. Conclusion: It is hoped that further efforts in this direction could lead to the identification and development of target-specific chemotherapeutic agents.