Background: Astrocytomas (sub-group of gliomas) are central neuron system malignant diseases, which are originated from astrocytes. There are several documents about molecular mechanism of astrocytomas and many related genes are introduced. Here, gene expression profile alteration for grade III relative to grade II of astrocytoma is analyzed via protein-protein interaction (PPI) network to screen and introduce critical differentially expressed genes (DEGs). Methods: The significant DEGs were extracted from gene expression omnibus (GEO) database and included in a PPI network by Cytoscape software. The common significant DEGs and central nodes of the network were selected and enriched by ClueGO to find related biological terms. Results: Twenty critical genes including zinc finger protein 765 (ZNF765), zinc finger protein 540 (ZNF540), Zeste white 10 (ZW10) ZW10 interacting kinetochore protein (ZWINT), collagen type XVIII alpha 1 chain (COL18A1), protamine 2 (RRM2), kinesin family member 23 (KIF23), minichromosome maintenance 10 (MCM10), anaphase promoting complex subunit 7 (ANAPC7), NADPH oxidase activator 1 (NOXA1), ryanodine receptor 2 (RYR2), myozenin 3 (MYOZ3), myosin binding protein C (MYBPC2), fast type, keratin 17 (KRT17), zinc phosphodiesterase ELAC protein 2 (ELAC2), Abelson helper integration site 1 (AHI1), latent transforming growth factor beta binding protein 1 (LTBP1), kaptin (actin binding protein) (KPTN), BEN domain containing 3 (BEND3), cysteine and histidine rich 1 (CYHR1), and hyaluronoglucosaminidase 2 (HYAL2) were identified. Eight class of biological terms related to the critical genes were determined and discussed. Conclusions: A wide range of the introduced significant genes indicates that there are several possible therapeutic ways to challenge astrocytoma.