Sediment is an important environmental matrix for pollution monitoring in aquatic environments. The San Francisco (SF) Bay is an endpoint for waters from the urbanized Bay Area and agricultural drainage from the Central Valley. The estuary has been impacted by chemical pollution from sources including stormwater runoff, wastewater treatment plants (WWTPs), legacy contamination, agricultural and industrial runoff. The study aims to determine chemicals exclusively found in the margin sediment compared to compounds found among ambient sediment in Upper South SF Bay and to identify and prioritize chemicals of emerging concern in Upper South SF Bay. In the Upper South Bay, seven margin and three ambient sediment samples were prepared using a QuEChERS method and analyzed by a non-targeted approach using comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC/TOF-MS). A total of 476 unique compounds were detected in this study. Of these compounds, 206 were tentatively identified based on their mass spectral similarity search through the NIST mass spectral library. A subset of 55 compounds were significantly more abundant in the margin sediment than ambient sediment. These compounds are classified to 24 groups based on their chemical structures: parent PAHs, alkyl-PAHs, alkyl-sulfur containing PAH, s-PAH, n-PAH, oxy PAH, PAH derivative, aryl alkyl ketone, cyclic ketone, polycyclic aromatic ketone, cyclic ketone, unsaturated cyclic ketone, ester, nitrile, pyridine, saturated fatty acid, aromatic azide, polyaromatic chrysene, tetralin, aromatic azide, arylamine, benzaldehyde derivative, methyl indole, and phthalate. The 55 compounds were examined for their frequency of detection, relative abundance, persistence, and bio-accumulative and toxicity (PBT) parameters. The 55 compounds were further prioritized by their (PBT) parameters using partial order ranking into 17 levels, where the compounds at level 17 are deemed the highest of concern. Using PBT partial order ranking combined with ubiquity and abundance data, we pinpointed nine priority compounds: 9H-fluorene, 2,3-dimethyl-; Phenanthrene, 1,7- dimethyl-; pyrene, 1,3- dimethyl; chrysene, 6-methyl; anthracene, 9-ethyl-; 2,7- dimethyldibenzothiophene; 11-H-benzo[a]fluoren-11-one; 11-H-benzo[a]fluoren-11-one; and Benzo(b)naphtho(1,2-d)furan. Of the 55 compounds, one is routinely monitored in the estuary indicating a data gap regarding unmonitored CECs. Further studies are required for the prioritized compounds with regards to their occurrence, toxicity and sources.