Non-pharmaceutical interventions (NPIs) have been proven effective in reducing the spread of the coronavirus disease 2019 (COVID-19), but their broader impact on gastrointestinal disorders remains poorly studied. Here, we report an observational analysis and retrospective study that compares the incidence of acute diarrheal diseases in Hangzhou, Zhejiang, China, between 2019 and 2020, with an examination of the antimicrobial resistance and genetic spectrum of non-typhoidal Salmonella (NTS) from 2015 to 2022, before and during the COVID-19 pandemic. Our findings underscore that NPIs related to COVID-19 effectively reduced the incidence of acute diarrhea, with a substantial decrease in most enteric pathogens. Notably, NTS exhibited an unexpected surge. Further genomic investigations of NTS isolates revealed an overall reduction in antimicrobial-resistant (AMR), disinfection-tolerant, and virulent capabilities, but with marked variations detected between human and animal isolates. Additional genome-based analysis confirmed a decrease in the scale of zoonotic transmission in response to NPIs, suggesting particular NTS types may contribute to human infections via alternative pathways. The collective findings manifested that COVID-19-related NPIs had a mixed impact on NTS infections, which may inform AMR NTS mitigation policy.