Diet‐induced obesity is associated with impaired B‐cell‐driven humoral immunity, which coincides with chronic inflammation and has consequences for responses to infections and vaccinations. Key nutritional, cellular, and molecular mechanisms by which obesity may impair aspects of humoral immunity such as B cell development, class switch recombination, and formation of long‐lived antibody secreting cells are reviewed. A key theme to emerge is the central role of white adipose tissue on the formation and function of pro‐inflammatory B cell subsets that exacerbate insulin resistance. The underlying role of select hormones such as leptin is highlighted, which may be driving the formation of pro‐inflammatory B cells in the absence of antigen stimulation. This review also extensively covers the regulatory role of lipid metabolites such as prostaglandins and specialized pro‐resolving mediators (SPMs) that are synthesized from polyunsaturated fatty acids. Notably, SPM biosynthesis is impaired in obesity and contributes toward impaired antibody production. Future directions for research, including avenues for therapeutic intervention, are included. This review covers experimental data on how obesity impairs key aspects of humoral immunity. Notably, results from human and rodent studies suggest that leptin may be driving B lymphocytes to become pro‐inflammatory and secrete auto‐antibodies. The review also discusses how metabolites derived from polyunsaturated fatty acids regulate antigen‐specific antibody levels.