<p>In this paper, we consider the well-posedness and regularity of the density-dependent Cahn–Hilliard–Navier–Stokes system in 2D. This model consists of the Navier–Stokes equations governing the fluid velocity and the Cahn–Hilliard equations related to the phase field. Given the highly nonlinear and multi-scale coupling characteristics of the system, we employ the Schauder fixed-point theorem to prove the existence of weak solutions. Using energy estimates and combining the Gagliardo–Nirenberg inequality, we enhance the regularity. The research results show that when the external force <InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\textbf{f}=\nabla g\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <mi mathvariant="bold">f</mi> <mo>=</mo> <mi mathvariant="normal">∇</mi> <mi>g</mi> </mrow> </math></EquationSource> </InlineEquation> and initial data belong to <InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(H^{3}(\Omega )\)</EquationSource> <EquationSource Format="MATHML"><math> <mrow> <msup> <mi>H</mi> <mn>3</mn> </msup> <mrow> <mo stretchy="false">(</mo> <mi mathvariant="normal">Ω</mi> <mo stretchy="false">)</mo> </mrow> </mrow> </math></EquationSource> </InlineEquation>, there exists a unique global weak solution for this system. This conclusion provides a strict mathematical basis for the simulation of multiphase flows with density differences.</p>