To address the limited solubility and applicability of conventional hydrocarbon surfactants in supercritical CO2, a series of multi-ester headgroup surfactants were designed and synthesized by leveraging the CO2-philic properties of ester groups. The molecular structures were characterized using Fourier transform infrared (FT-IR) spectroscopy and 1H NMR. A custom-designed laser-based apparatus was developed to quantify surfactant solubility and systematically investigate phase behavior in CO2. Molecular dynamics (MD) simulations were employed to elucidate structure–solubility relationships across multiple scales, including solubility parameters, interaction energies, radial distribution functions (RDFs), and free volume fractions. Results indicate that, at 323.15 K, the cloud-point pressure of a 1 wt% multi-ester headgroup surfactant in CO2 is below 12 MPa. This value is substantially lower than the typical minimum miscibility pressure (MMP) between crude oil and CO2 in Chinese reservoirs. The number and arrangement of ester groups synergistically affect solubility, with linear configurations outperforming cyclic ones and an optimal ester count (n = 5) maximizing solubility. Surfactant–CO2 interactions are primarily governed by van der Waals and electrostatic forces, with van der Waals contributions exceeding 70%. RDF analysis reveals that carbonyl oxygen (O1) and terminal methyl carbon (C1) in the ester group are the primary CO2 binding sites, enhancing CO2-philicity via Lewis acid–base (LA–LB) and dispersion interactions. Linear ester side chains exhibit enhanced flexibility and conformational adaptability. The free volume fraction initially increases and then decreases with increasing ester group count, with the optimal configuration (MEG-L5) showing maximal chain extension and CO2 contact efficiency during dissolution. Given that hydrocarbon surfactants primarily interact with CO2 through LA–LB and dispersion forces, the design focus is on optimizing the density and arrangement of CO2-philic segments. This modulates entropy changes to enhance favorable enthalpic interactions. This study elucidates the dissolution mechanisms of multi-ester headgroup surfactants in supercritical CO2 (scCO2) and identifies the molecular factors controlling their CO2-philicity. These insights provide a theoretical basis for designing green, fluorine-free, cost-effective CO2-philic surfactants for enhanced oil recovery.