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A lot of oil is leaked into aquatic environments, significantly impacting fish health and, consequently, human populations. This study aimed to introduce an L-phenylalanine-based low-molecular-weight gelator (expressed as Z-Phe-C18) as a smart remediation tool for oil spills. Several groups of Nile tilapia were allocated in aquaria exposed to different doses of crude engine oil with/without the organogelator for 4 weeks. The results revealed a significant increase in biochemical oxygen demand, chemical oxygen demand, electrical conductivity, and total dissolved solids in water samples of fish aquaria exposed to oil pollution. The antioxidant activity levels, micronucleus formation, and expression patterns of stress-related genes were significantly higher in the livers of fish exposed to crude oil than in those of control fish. On the contrary, fish groups exposed to oil pollution and treated with the organogelator indicated that antioxidant enzymes, micronucleus incidence, and gene expression alteration of stress-related genes declined compared with those exposed to oil pollution only. The results suggest that oil pollution can induce oxidative stress via the enhancement of oxygen free radical formation. On the contrary, oil removal by the organogelator decreases oxidative stress and consequently strengthens fish immunity. So, we can conclude that organogelator treatment is promoting oxidative resistance development by increasing the activities of antioxidant enzymes, which are important in protection against oil pollution and preventing peroxidation of fish tissues. Promisingly, the organogelator could be used as a tool for the remediation of oil pollution in aquatic environments. [ABSTRACT FROM AUTHOR]