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This review focuses on the role of oxidized sterols in three major gastrointestinal cancers (hepatocellular carcinoma, pancreatic, and colon cancer) and how the circadian clock affects the carcinogenesis by regulating the lipid metabolism and beyond. While each field of research (cancer, oxysterols, and circadian clock) is well-studied within their specialty, little is known about the intertwining mechanisms and how these influence the disease etiology in each cancer type. Oxysterols are involved in pathology of these cancers, but final conclusions about their protective or damaging effects are elusive, since the effect depends on the type of oxysterol, concentration, and the cell type. Oxysterol concentrations, the expression of key regulators liver X receptors (LXR), farnesoid X receptor (FXR), and oxysterol-binding proteins (OSBP) family are modulated in tumors and plasma of cancer patients, exposing these proteins and selected oxysterols as new potential biomarkers and drug targets. Evidence about how cholesterol/oxysterol pathways are intertwined with circadian clock is building. Identified key contact points are different forms of retinoic acid receptor related orphan receptors (ROR) and LXRs. RORs and LXRs are both regulated by sterols/oxysterols and the circadian clock and in return also regulate the same pathways, representing a complex interplay between sterol metabolism and the clock. With this in mind, in addition to classical therapies to modulate cholesterol in gastrointestinal cancers, such as the statin therapy, the time is ripe also for therapies where time and duration of the drug application is taken as an important factor for successful therapies. The final goal is the personalized approach with chronotherapy for disease management and treatment in order to increase the positive drug effects.