This study aimed to identify the biological processes associated with long-term survival in high-grade serous ovarian cancer (HGSOC). HGSOC cases obtained from The Cancer Genome Atlas Ovarian Cancer (TCGA-OV) database were divided into long-term survivors (LTS) and normal-term survivors (NTS) based on survival cutoffs defined by the HGSOC cohort in the SEER database. Differentially expressed genes (DEGs) were screened using the generalized linear modeling (GLM) method. Gene Ontology (GO) functional and KEGG pathway enrichment analyses were performed using DAVID Bioinformatics Resources. DEG-related protein-protein interactions (PPI) were extracted from the STRING database and hub genes were identified using CytoHubba in the Cytoscape program. In total, 157 DEGs, including 155 upregulated and 2 downregulated genes, were identified. Upregulated genes were statistically enriched in 80 GO terms and 11 KEGG pathways related to energy and substrate metabolism, such as protein absorption, digestion, and metabolism as well as signaling pathways, including chromatin silencing, regulation of ERK1 and ERK2 cascade, and regulation of MAPKKK. ALB and POMC were the common hub genes. These findings reveal that protein anabolism is crucial to long-term survival, regulated by activation of the MAPK/ERK signaling pathway and chromatin silencing. Comprehensive understanding of the molecular mechanisms via further exploration may contribute toward an effective treatment for ovarian cancer. Copyright © 2020. Published by Elsevier Inc.