Activity-dependent changes in neuronal function require coordinated regulation of the protein synthesis and protein degradation machinery to maintain protein homeostasis, critical to proper neuronal function. However, the biochemical evidence for this balance and coordination remains poorly understood and largely underexplored. Leveraging our recent discovery of a neuronal-specific 20S membrane proteasome complex (NMP), we began exploring how neuronal activity regulates its function. Remarkably, we observed polypeptides being synthesized during neuronal stimulation were rapidly turned over by the NMP. This turnover correlated with enhanced production of NMP-derived peptides in the extracellular space. Using parameters determined in these experiments, we constructed Markov process chain models in silico which predicted that the kinetics of this process necessitate coordination of translation and degradation. In a series of biochemical analyses, this predicted coordination was instantiated by NMP-mediated and ubiquitin-independent degradation of ribosome-associated nascent polypeptides. Using in-depth, global, and unbiased mass spectrometry, we identified the nascent protein substrates of the NMP. Among these substrates, we found that immediate-early gene products c-Fos and Npas4 were targeted to the NMP during ongoing activity-dependent protein synthesis, prior to activity-induced transcriptional responses. We propose that these findings generally define an activity-dependent protein homeostasis program through the NMP that selectively targets nascent polypeptides prior to adopting their final functional conformations.