Heavy crude oil contains high levels of asphaltenes, which tend to aggregate and deposit in reservoir pores and pipelines, severely hindering recovery, transportation, and refining. To address the challenge of enhancing asphaltene stability and preventing operational blockage, a green, low-toxicity natural deep eutectic solvent (NaDES) composed of thymol and tetradecylamine (TDA) was developed in this study. This solvent exhibits a high asphaltene solubility of ∼75 mg/mL at 25 °C. Density-functional theory (DFT) calculations revealed that the dissolution is governed by hydrogen bonding (notably between –NH2 in NaDES and S=O in asphaltene) and dispersive interactions. Key mechanisms include interfacial adhesion and wetting (adhesion force of −6.7 nN, contact angle of ∼0°), penetration and diffusion (diffusion area ratio of 4.5), layer-to-layer exfoliation into micro-nano sheets, and improved dispersion stability. Microfluidic experiments in rough asphaltene-filled channels further demonstrated flow-dependent dissolution pattern transition from wedge-shaped to uniform, accompanied by significant surface smoothing. This work presents an efficient and sustainable NaDES-based strategy to mitigate asphaltene deposition in heavy oil production and transportation, supporting higher resource recovery, lower operational costs, and improved process sustainability.