Glucocorticoids (GCs) are effective in treating autoimmune and inflammatory disorders but come with significant side effects, many of which are mediated by non-immunological cells. Therefore, there is rapidly growing interest in using antibody drug conjugate (ADC) technology to deliver GCs specifically to immune cells, thereby minimizing off-target side effects. Herein, we report the study of anti-CD11a, anti-CD38, and anti-TNFα ADCs to deliver dexamethasone to monocytes. We found that anti-CD11a and anti-CD38 were rapidly internalized by monocytes, while uptake of anti-TNFα depended on pre-activation with LPS. Using these antibodies were attached to a novel linker system, ValCitGlyPro-Dex (VCGP-Dex), that efficiently released dexamethasone upon lysosomal catabolism. This linker relies on lysosomal cathepsins to cleave after the ValCit sequence, thereby releasing a GlyPro-Dex species that undergoes rapid self-immolation to form dexamethasone. The resulting monocyte-targeting ADCs bearing this linker payload effectively suppressed LPS-induced NFκB activation and cytokine release in both a monocytic cell line (THP1) and in human PBMCs. Anti-TNFα_VCGP-Dex and anti-CD38_VCGP-Dex were particularly effective, suppressing ∼60–80% of LPS-induced IL-6 release from PBMCs at 3–10 μg mL−1 concentrations. In contrast, the corresponding isotype control ADC (anti-RSV) and the corresponding naked antibodies (anti-CD38 and anti-TNFα) resulted in only modest suppression (0–30%) of LPS-induced IL-6. Taken together, these results provide further evidence of the ability of glucocorticoid-ADCs to selectively suppress immune responses, and highlight the potential of two targets (CD38 and TNFα) for the development of novel immune-suppressing ADCs.