Post-hydrothermal liquefaction wastewater (PHW) is a byproduct of the hydrothermal liquefaction (HTL) process. Previous research indicates that PHW is free of pathogens and contains nutrients needed for crop growth, but may contain metal(loid)s. This study evaluated the ability of differentially treated PHW for effective and safe hydroponic lettuce production. Water containing only hydroponic fertilizer (Source Water 1) had the highest total dry yield of all five treatments; 3.1 times higher than Source Water 2 (diluted PHW with sand filtration), 3.5 times higher than Source Water 3 (diluted PHW with sand + carbon filtration), 2.6 times higher than Source Water 4 (diluted and nitrified PHW with sand filtration), and 1.3 times higher than Source Water 5 (diluted PHW supplemented with hydroponic fertilizer). Findings also indicated that while PHW was below the US Department of Agriculture Foreign Agriculture Service maximum levels for cadmium, lead, and mercury in food, the concentration of arsenic was 1.6, 2.4, and 2.0 times higher than the maximum level for Source Waters 2, 3, and 4, respectively. There was no detectable E. coli or fecal coliforms in any of the treated PHW. While nitrogen was present in the raw PHW, only 0.03% was NO3-N and NO2-N. Diluted PHW supplemented with hydroponic fertilizer had lower lettuce yield than hydroponic fertilizer alone, indicating a potential non-nutrient inhibition of plant growth by PHW. Therefore, this research demonstrates that treated PHW does not pose a biological contamination risk for lettuce, but may entail levels of arsenic in edible leaf tissues that are in excess of safe levels. Additional treatment of PHW can benefit crop production by allowing crop utilization of a greater fraction of total nitrogen in the raw PHW.