As it is known that SARS-CoV-2 invades the mitochondria of neural cells, a plasma technique for measuring central nervous system proteins in living individuals were utilized to explore the neuropathogenic mechanisms of long-COVID-19. Quantification of SARS-CoV-2 proteins and mitochondrial proteins (MPs) in enriched plasma neuron-derived extracellular vesicles (NDEVs) and astrocyte-derived extracellular vesicles (ADEVs) was performed in resolved acute COVID-19 without post-acute sequelae of SARS-CoV-2 (PASC), PASC without neuropsychiatric manifestations (NP), PASC with NP, and healthy controls. NDEV and ADEV mean levels of SARS-CoV-2 S1 and nucleocapsid (N) proteins were greater in all PASC subgroups than in controls, while only N levels were higher in PASC with NP compared to those without NP. Exosome marker CD81-normalized NDEV mean levels of subunit 6 of MP respiratory chain complex I and subunit 10 of complex III, as well as neuroprotective MPs Humanin and mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), were all significantly decreased in PASC with NP relative to controls, but not in PASC without NP. NDEV levels of MPs voltage-dependent anion-selective channel protein 1 (VDAC1) and N-methyl-D-aspartate receptor 1 (NMDAR1) were reduced in PASC without and with NP. In contrast, those of calcium channel MPs mitochondrial calcium uniporter (MCU), sodium/calcium exchanger (NCLX), and leucine zipper EF-hand containing transmembrane 1 protein (LETM1) were reduced only in PASC with ADEV concentrations of MCU and NCLX were only elevated in PASC without and with NP. Abnormal NDEV and ADEV levels of SARS-CoV-2 N and S1 protein and MPs correlate with NP and could serve as biomarkers for long-term COVID prognosis and treatment trials.