<p>Understanding the seasonality of respiratory syncytial virus (RSV) is crucial for cost-effective seasonal RSV prophylaxis administration. The impact of short-term changes in air pollution and meteorological factors on RSV epidemics, particularly their spatial variations, remains unclear. We conducted a time-series analysis to investigate the association between short-term environmental changes and weekly RSV infection in Chile. Weekly data on the number of new laboratory RSV tests and confirmed RSV-positive cases, meteorological factors, and air pollutants were collected from 16 Chilean regions (2015–2018). We fitted a quasi-Poisson regression to evaluate the link between short-term environmental changes and RSV infection in each region. We utilized random effects meta-analyses to pool the region-specific estimates. Subgroup analyses were further conducted to assess variations by socio-economic and geographical context. Nationwide associations were observed between weekly average temperature and RSV activity, with a 1 °C increase being positively associated with an 8.2% (95% confidence interval: 0.87–0.97) decrease in RSV positivity at a lag of 3 weeks. In addition, we found significant positive nationwide associations between air pollutants, i.e., nitrogen dioxide (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\({{\rm{NO}}}_{2}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="normal">NO</mi> </mrow> <mrow> <mn>2</mn> </mrow> </msub> </math></EquationSource> </InlineEquation>) and particulate matter smaller than 2.5 μm (<InlineEquation ID="IEq2"> <EquationSource Format="TEX">\({{\rm{PM}}}_{2.5}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="normal">PM</mi> </mrow> <mrow> <mn>2.5</mn> </mrow> </msub> </math></EquationSource> </InlineEquation>), and RSV activity. A 5-<InlineEquation ID="IEq3"> <EquationSource Format="TEX">\({\rm{\mu }}{\rm{g}}/{{\rm{m}}}^{3}\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mrow> <mi mathvariant="normal">μ</mi> <mi mathvariant="normal">g</mi> </mrow> <mo>/</mo> <mrow> <msup> <mrow> <mi mathvariant="normal">m</mi> </mrow> <mrow> <mn>3</mn> </mrow> </msup> </mrow> </mrow> </math></EquationSource> </InlineEquation> increase in <InlineEquation ID="IEq4"> <EquationSource Format="TEX">\({{\rm{PM}}}_{2.5}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="normal">PM</mi> </mrow> <mrow> <mn>2.5</mn> </mrow> </msub> </math></EquationSource> </InlineEquation> and <InlineEquation ID="IEq5"> <EquationSource Format="TEX">\({{\rm{NO}}}_{2}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="normal">NO</mi> </mrow> <mrow> <mn>2</mn> </mrow> </msub> </math></EquationSource> </InlineEquation> concentrations was positively associated with an increase in RSV positivity of 3.4% (1.00–1.06) and 10.2% (1.05–1.15) at lags of 3 weeks, respectively. We also observed regional variations of environmental impacts on RSV activity across Chile, including <InlineEquation ID="IEq6"> <EquationSource Format="TEX">\({{\rm{PM}}}_{2.5}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="normal">PM</mi> </mrow> <mrow> <mn>2.5</mn> </mrow> </msub> </math></EquationSource> </InlineEquation> and particulate matter smaller than 10 micrometers (<InlineEquation ID="IEq7"> <EquationSource Format="TEX">\({{\rm{PM}}}_{10}\)</EquationSource> <EquationSource Format="MATHML"><math> <msub> <mrow> <mi mathvariant="normal">PM</mi> </mrow> <mrow> <mn>10</mn> </mrow> </msub> </math></EquationSource> </InlineEquation>). The study suggests that improving air quality could potentially lower the RSV activity, especially in highly polluted areas. Furthermore, temperature and air quality changes may be used for predicting short-term shifts in RSV activity, informing RSV prevention efforts.</p>