Coastal and estuarine ecosystems fringing the North Pacific Ocean are particularly vulnerable to ocean acidification, hypoxia, and intense marine heatwaves as a result of interactions among natural and anthropogenic processes. Here, we characterize variability during a seasonally resolved cruise time series (2014–2018) in the southern Salish Sea (Puget Sound, Strait of Juan de Fuca) and nearby coastal waters for select physical (temperature, T; salinity, S) and biogeochemical (oxygen, O₂; carbon dioxide fugacity, fCO₂; aragonite saturation state, Ω_arag) parameters. Medians for some parameters peaked (T, Ω_arag) in surface waters in summer, whereas others (S, O₂, fCO₂) changed progressively across spring–fall, and all parameters changed monotonically or were relatively stable at depth. Ranges varied considerably for all parameters across basins within the study region, with stratified basins consistently the most variable. Strong environmental anomalies occurred during the time series, allowing us to also qualitatively assess how these anomalies affected seasonal patterns and interannual variability. The peak temperature anomaly associated with the 2013–2016 northeast Pacific marine heatwave–El Niño event was observed in boundary waters during the October 2014 cruise, but Puget Sound cruises revealed the largest temperature increases during the 2015–2016 timeframe. The most extreme hypoxia and acidification measurements to date were recorded in Hood Canal (which consistently had the most extreme conditions) during the same period; however, they were shifted earlier in the year relative to previous events. During autumn 2017, after the heat anomaly, a distinct carbonate system anomaly with unprecedentedly low Ω_arag values and high fCO₂ values occurred in parts of the southern Salish Sea that are not normally so acidified. This novel “CO₂ storm” appears to have been driven by anomalously high river discharge earlier in 2017, which resulted in enhanced stratification and inferred primary productivity anomalies, indicated by persistently and anomalously high O₂, low fCO₂, and high chlorophyll. Unusually, this CO₂ anomaly was decoupled from O₂ dynamics compared with past Salish Sea hypoxia and acidification events. The complex interplay of weather, hydrological, and circulation anomalies revealed distinct multi-stressor scenarios that will potentially affect regional ecosystems under a changing climate. Further, the frequencies at which Salish cruise observations crossed known or preliminary species’ sensitivity thresholds illustrates the relative risk landscape of temperature, hypoxia, and acidification anomalies in the southern Salish Sea in the present day, with implications for how multiple stressors may combine to present potential migration, survival, or physiological challenges to key regional species. The Salish cruise data product used in this publication is available at https://doi.org/10.25921/zgk5-ep63 (Alin et al., 2022), with an additional data product including all calculated CO₂ system parameters available at https://doi.org/10.25921/5g29-q841 (Alin et al., 2023).