Among reared bivalves, some “novel species”, such as the great scallop, Pecten maximus, have experienced more difficulty with routine reproduction due to their high sensitivity to biological, chemical, and physical stress during stages of early development. Working with high larval densities requires the use of aeration systems to provide optimal larval suspension and feed distribution. The high susceptibility of the great scallop to aeration in small-volume systems may impose an important limitation in hatchery-based practices. The present study aimed to investigate the processes impacted by aeration in P. maximus veliger larvae exposed to continuous aeration in small-volume tanks (10 L). Aeration appeared as major stressor that was responsible for early mortality among exposed animals (at 96 h after aeration started, haa) when exposure started 13 days after fertilization. Exposed larvae and controls were collected at 12, 24 and 72 haa, and a total of 18 cDNA libraries, each representing a pool of approximately 7,500 larvae, were sequenced, obtaining 358,817,016 raw reads. RNA-seq data were first used to build a de novo transcriptome assembly, and differential transcript abundance was assessed in exposed and control groups; thus, the molecular mechanisms involved in high sensitivity to aeration were deciphered. More than 2,000 transcripts were differentially expressed between exposed and control larvae across the entire time series (logFC > 1, FDR < 5%). Functional analysis revealed that transcriptional changes in larvae exposed to aeration mainly involved the genes that regulate digestive activity and energy metabolism, immune defense, inflammation, apoptosis, larval growth, and development. The results of this study demonstrate that, overall, aeration affects the feeding capacity and energy metabolism of larvae, with expected consequences on the animal's fitness, including its swimming efficiency. Aeration also triggered immune responses and apoptosis, which then increased through opportunistic infections. Notably, infections may be a consequence of a bacterial bloom triggered by the first mortality events that occurred in the culture. This study provides insights into the interactions between environmental variables and great scallop larvae physiology, and the results may contribute to the development of strategies for improving larval rearing practices and ensuring long-term sustainability of P. maximus aquaculture.