Water solubility of hydrophobic drugs is pivotal for their bioavailability in pharmaceutics and cosmetics. Methods to improve drug solubility, including detergents, correlate with bacterial damage, gut dysbiosis, and common diseases. Strategies that decouple drug solubility from antibacterial potency are crucially needed. To better align detergent chemistry with consumer health, we establish a covalent solubilization strategy by connecting a single drug molecule with a detergent molecule through a covalent bond. In such a conjugate, drug and detergent will co-diffuse, enabling water solubility, independently of additional detergent molecules. For conjugation, we designed an asymmetric hybrid detergent with an independently addressable functional handle for conjugation. Compared to conventional solubilization strategies with detergent micelles, our drug-detergent conjugate exhibits surprising properties. First, the covalent solubilization strategy requires only a single detergent molecule to solubilize one drug molecule. Drug solubilization is enabled with unprecedented efficiency even at sub-micellar concentrations, as confirmed by spectroscopy, dynamic light scattering, and cryo-electron microscopy. Second, the covalent solubilization strategy can decouple drug solubility from antibacterial potency. Detergent conjugation consistently reduces drug potency against bacteria relevant to human gut health whose growth is otherwise impaired by the parent drug, as confirmed by microbiological tests. Third, the covalent solubilization strategy can endow hydrophobic drugs with unusually potent lipid bilayer permeabilizing properties. This surprising property arises from a synergy between flexible and rigid structural elements that are commonly found in detergents and drugs. It highlights the relevance of covalent solubilization for applications in which lipid membranes limit drug efficacy, as frequently observed in the development of anticancer drugs. We expect the concept can be widely extended to drugs and detergents that contain independently addressable functional groups for covalent conjugation. In summary, our findings highlight a covalent detergent solubilization strategy as a starting point for tuning bioavailability and microbiome compatibility of pharmaceutical and cosmetical formulations.