Global food production, both aquatic and terrestrial, is rife with sustainability issues. Aquaculture is a rapidly growing industry that is on track to surpass wild-caught fishery production by 2030. The integration of aquaculture and agriculture systems could help to reduce some of their respective and shared environmental issues. Integrated Aquaculture–Agriculture (IAA) has been shown to provide a variety of benefits to both aquaculture and agriculture including increased system water use efficiency (WUE), a reduction in fertilizer use, and increases in total farm yield and resilience. This study was performed to examine the potential for rainbow trout aquaculture effluent to improve the yield, nutrient composition, and WUE of lettuce, as well as act as a partial fertilizer replacement. We used four irrigation treatments throughout the experiment: city water, aquaculture effluent, city water with added organic fertilizer, and aquaculture effluent with added organic fertilizer. Throughout the trial, there were some issues of herbivory in the growing plot, but overall, the lettuce receiving city water with organic fertilizer (30. ± 3.4 g/plant) showed significantly higher fresh biomass than effluent treatments (18 ± 1.4 g/plant and 17 ± 2.9 g/plant) at the end of the trial. We did not detect any significant differences among treatments in the macro- and micronutrients of the lettuce shoots and roots. However, the WUE of effluent treatments (4.4 ± 0.030 kg/m³ and 1.0 ± 0.070 kg/m³) was greater than that of organic fertilizer (0.28 ± 0.050 kg/m³) and control treatments (0.23 ± 0.040 kg/m³). The results indicate that adopting IAA in California could improve statewide WUE and conserve water for sustainable agricultural production.