Objective To analyze the clinical characteristics and explore the potential mechanisms underlying acute wheezing associated with respiratory syncytial virus （RSV） and human rhinovirus （HRV） infections in infants. Methods A retrospective analysis was conducted on 560 infants who consecutively presented to the emergency department of Qingdao University Affiliated Women and Children's Hospital between January 2022 and December 2024 with acute exacerbation of wheezing caused by RSV and/or HRV infection； these infants constituted the infection group. A control group of 120 healthy infants who underwent routine physical examinations at the same hospital during the same period was also included. Multiplex PCR amplification sequencing technology was employed to detect respiratory pathogens via nucleic acid analysis. The infection group was further classified into the RSV-only group （n = 248）， the HRV-only group （n = 186）， and the co-infection group （HRV + RSV， n = 126）. One-way analysis of variance （ANOVA） was used to compare body mass index （BMI）， peripheral blood white blood cell （WBC） count， neutrophil count， lymphocyte count， C-reactive protein （CRP） levels， and concentrations of interleukin （IL）-1β， IL-6， Toll-like receptor 4 （TLR4）， NOD-like receptor protein 3 （NLRP3） inflammasome， and matrix metalloproteinase-9 （MMP-9） across the groups. Additionally， comparisons were made regarding gender distribution， severity of wheezing， history of wheezing， history of eczema， parental allergic history， oxygen supplementation requirements， and presence of concurrent pulmonary infection among the infected infants. Based on wheezing severity， the infection group was further divided into a severe wheezing group and a mild wheezing group. Clinical characteristics and biological indicators were analyzed and compared between these two groups to identify potential independent risk factors. Pearson correlation analysis was performed to evaluate the association between peripheral blood levels of IL-6， NLRP3， and MMP-9 and the severity of acute wheezing exacerbation in children. Results A one-way ANOVA indicated statistically significant differences in WBC count， neutrophil count， CRP， IL-1β， IL-6， TLR4， NLRP3， and MMP-9 levels across the study groups （all P < 0.001）. Both the RSV and co-infection groups demonstrated significantly higher rates of severe wheezing， oxygen requirement， and prolonged wheezing duration compared to the HRV group （all P < 0.05）. Among these， the co-infection group exhibited the highest oxygen requirement rate， although the duration of wheezing was shorter than that observed in the RSV group （P < 0.05）. The incidence of concurrent pulmonary infection was significantly greater in the RSV group compared to the HRV group （P < 0.05）. Additionally， the proportion of infants with a prior history of wheezing was significantly higher in the RSV group than in both the HRV and co-infection groups （P < 0.05）. Both the RSV and co-infection groups showed a significantly higher prevalence of eczema history among infants compared to the HRV group （P < 0.05）. Moreover， the co-infection group had a significantly higher proportion of parental allergic history compared with both the RSV and HRV groups （P < 0.05）. Clinical data analysis stratified by wheezing severity revealed that RSV was the most commonly detected virus among the enrolled infants， particularly in those presenting with severe wheezing （χ2 = 3.940， P = 0.002）. The severe wheezing group exhibited significantly higher rates of prior wheezing， history of eczema， parental allergy， need for oxygen supplementation， and concurrent pulmonary infections compared to the mild wheezing group （P < 0.001）. Furthermore， the duration of wheezing was significantly prolonged in the severe group relative to the mild group （t = 2.058， P = 0.040）. Levels of IL-6， NLRP3， and MMP-9 were also significantly elevated in the severe wheezing group （P < 0.05）. Multivariate logistic regression analysis revealed that RSV infection， along with elevated levels of IL-6， NLRP3， and MMP-9， were independent risk factors associated with severe wheezing （OR = 3.217， 1.023， 1.022， and 1.056， respectively； all P < 0.05）. In children with RSV/HRV infection， the severity of acute wheezing demonstrated a positive correlation with NLRP3 and MMP-9 levels （P < 0.05）. The Pearson correlation coefficient between NLRP3 and MMP-9 was r = 0.238 （P < 0.001）， indicating a weak yet statistically significant positive relationship. Conclusions RSV may provoke more severe respiratory inflammatory responses and clinical manifestations compared to HRV. Individuals with a genetic predisposition to allergies or a pre-existing history of respiratory conditions may experience heightened severity of wheezing following viral infection. The NLRP3 inflammasome may further intensify airway inflammation and remodeling through the promotion of MMP-9 release. These mechanisms may collectively contribute to the pathogenesis of acute wheezing episodes and subsequently influence the progression of respiratory diseases.