Proteins often experience various stresses which restrict industrial applications. The solvent is one of the most important external factors, and a detrimental solvent effect may lead to irreversible protein unfolding, inactivation of enzymes, and/or formation of aggregates. Although aqueous buffer salts are widely used as solvents, proteins still suffer from insufficient protein stability and solubility, as well as the high volatility in the aqueous solutions. Ionic liquids (ILs) are liquids that are comprised entirely of ions and have been shown to profoundly regulate protein properties and functionalities. This work presents the solvent effect of a range of ILs on different globular proteins including lysozyme, green fluorescent protein, β-lactoglobulin, myoglobin, trypsin and pepsin. We employ small angle X-ray scattering (SAXS) to investigate the effect of a range of IL systems on the proteins. The protein properties such as size, shape, conformational changes, compactness and aggregation are discussed. The results show that the acetate anion can retain protein folding more than the mesylate anion. In addition, we use size exclusion chromatography (SEC)-SAXS to explore the protein aggregation and conformational changes. We further employ modelling tools including CRYSOL, GASBOR and SREFLEX to reconstruct and model protein structure and understand the solvent effect on protein behaviours at an atomic level. This study can improve our understanding of protein misfolding and aggregation and pave the way to design solvents to control the protein behaviours.