Nonspecific adsorption (NSA) impacts the performance of biosensors in complex samples. Coupled electrochemical–surface plasmon resonance biosensors (EC-SPR) offer interesting opportunities to evaluate NSA. This review details the main solutions to minimize fouling in electrochemical (EC), surface plasmon resonance (SPR) and EC-SPR biosensors. The discussion was centered on blood, serum and milk as examples of complex matrices. Emphasis was placed on antifouling coatings, NSA evaluation protocols and universal functionalization strategies to obtain antifouling biosensors. In the last 5 years, various antifouling coatings were developed for EC biosensors, including new peptides, cross-linked protein films and hybrid materials. Due to the comparatively much more scarce literature, for SPR and EC-SPR biosensors the discussion was extended to the early 2010s. The analysis revealed a wide range of antifouling materials with tunable conductivity, thickness and functional groups that can be tested in the future with EC-SPR. The high-throughput screening of new materials, molecular simulations and machine learning-assisted evaluations will even further widen the range of antifouling materials available for biosensors. The minimization of NSA’s impact on the analytical signal is moreover facilitated by unique sensing mechanisms associated with the bioreceptor or the particularities of the detection method. It is hoped that this review will encourage research in the field of EC-SPR biosensors.