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Unlike other coronaviruses, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly infected the global population, with some suffering long-term effects. Thanks to extensive data on SARS-CoV-2 made available through global, multi-level collaborative research, investigators are getting closer to understanding the mechanisms of SARS-CoV-2 infection. Here, using publicly available total and small RNAseq data of Calu3 cell lines, we conducted a comparative analysis of the changes in tRNA fragments (tRFs; regulatory small noncoding RNAs) in the context of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 infections. We found extensive upregulation of multiple tRFs in SARS-CoV-2 infection that was not present in SARS-CoV or other virus infections our group has studied. By comparing the total RNA changes in matching samples, we identified significant downregulation of TRDMT1 (tRNA methyltransferase), only in SARS-CoV-2 infection, a potential upstream event. We further found enriched neural functions among downregulated genes with SARS-CoV-2 infection. Interestingly, theoretically predicted targets of the upregulated tRFs without considering mRNA expression data are also enriched in neural functions such as axon guidance. Based on a combination of expression data and theoretical calculations, we propose potential targets for tRFs. For example, among the mRNAs downregulated with SARS-CoV-2 infection (but not with SARS-CoV infection), SEMA3C is a theoretically calculated target of multiple upregulated tRFs and a ligand of NRP1, a SARS-CoV-2 receptor. Our analysis suggests that tRFs contribute to distinct neurological features seen in SARS-CoV-2.