The biological productivity of river-dominated estuaries is affected strongly by variation in freshwater inflow, which affects nursery habitat quality. Previous research has shown this is generally true in the upper San Francisco Estuary, California, USA; however, one endemic species of high management importance, delta smelt (Hypomesus transpacificus), has shown ambiguous population responses to river inflow variation. We hypothesized that population-level associations with abiotic habitat metrics have not been apparent because the effects occur seasonally, and at spatial scales smaller than the entire upper San Francisco Estuary. We tested this hypothesis by applying regression techniques and principal components analysis (PCA) to a long-term data-set (1970–2004) of summertime fish catch, and concurrently measured water quality (specific conductance, Secchi disk depth, and water temperature). We found that all three water quality variables predicted delta smelt occurrence, and we identified three distinct geographic regions that had similar long-term trends in delta smelt capture probabilities. The primary habitat region was centered on the confluence of the Sacramento and San Joaquin rivers; delta smelt relative abundance was typically highest in the Confluence region throughout the study period. There were two marginal habitat regions—including one centered on Suisun Bay—where specific conductance was highest and delta smelt relative abundance varied with specific conductance. The second marginal habitat region was centered on the San Joaquin River and southern Sacramento-San Joaquin Delta. The San Joaquin region had the warmest water temperatures and the highest water clarity, which increased strongly in this region during 1970–2004. In the San Joaquin region, where delta smelt relative abundance was correlated with water clarity, catches declined rapidly to zero from 1970–1978 and remained consistently near zero thereafter. However, when we combined these regional results into estuary-wide means, there were no significant relationships between any of the water quality variables and delta smelt relative abundance. Our findings support the hypothesis that basic water quality parameters are predictors of delta smelt relative abundance, but only at regional spatial scales.