The Pearl River Estuary (PRE) is one of the major fishing grounds for the squid Uroteuthis chinensis. Taking that into consideration, this study analyzes the environmental effects on the spatiotemporal variability of U. chinensis in the PRE, on the basis of the Generalized Additive Model (GAM) and Clustering Fishing Tactics (CFT), using satellite and in situ observations. Results show that 63.1% of the total variation in U. chinensis Catch Per Unit Effort (CPUE) in the PRE could be explained by looking into outside factors. The most important one was the interaction of sea surface temperature (SST) and month, with a contribution of 26.7%, followed by the interaction effect of depth and month, fishermen’s fishing tactics, sea surface salinity (SSS), chlorophyll a concentration (Chl a), and year, with contributions of 12.8%, 8.5%, 7.7%, 4.0%, and 3.1%, respectively. In summary, U. chinensis in the PRE was mainly distributed over areas with an SST of 22–29 °C, SSS of 32.5–34‰, Chl a of 0–0.3 mg × m−3, and water depth of 40–140 m. The distribution of U. chinensis in the PRE was affected by the western Guangdong coastal current, distribution of marine primary productivity, and variation of habitat conditions. Lower stock of U. chinensis in the PRE was connected with La Niña in 2008.