The common bed bug, Cimex lectularius L. (Hemiptera: Cimicidae), is an obligate hematophagous insect that has resurged worldwide since the early 2000s. Bed bug control is largely based on the widespread, intensive application of pyrethroid-based insecticide formulations, resulting in the emergence of insecticide-resistant bed bug populations. Insecticide resistance is frequently linked to metabolic detoxification enzymes such as cytochrome monooxygenase (P450s), esterases, glutathione S-tranferase, and carboxylesterase. Therefore, one way to overcome insecticide resistance could be the formulation of insecticides with synergists that counteract metabolic resistance. To test this hypothesis, we evaluated the impact of four synergists—piperonyl butoxide (PBO), diethyl maleate (DEM), S,S,S-tributyl phosphorotrithioate (DEF), and triphenyl phosphate (TPP)—on deltamethrin efficacy in two pyrethroid-resistant bed bug strains. A statistically significant difference in synergism ratios (SR) of a highly resistant field-derived strain (Jersey City, resistance ratio [RR] = 20,000) was noted when any of the four synergists (PBO SR = 20.5; DEM SR = 11.7; DEF SR = 102.3; and TPP SR = 9.7) were used with deltamethrin. In a less deltamethrin-resistant strain, Cincinnati (RR = 3,333), pretreatment with PBO and DEM significantly synergized deltamethrin (PBO SR = 158.8; DEM = 58.8), whereas application of DEF and TPP had no synergistic effect. The synergism data collected strongly suggest that detoxification enzymes play a significant role in the metabolic mechanisms that mediate deltamethrin resistance in bed bugs. The development and use of safe metabolic synergists that suppress detoxification enzymes offers an interesting avenue for the management of insecticide-resistant field populations.