Simple Summary:& nbsp;LPS is a well-known agent in cell line models, including U937 monocytes, for inducing acute inflammation (INF). It is not known whether antioxidant HCQ, through the inhibition of TRPV1 in U937, can decrease oxidative monocyte toxicity and cell death. We investigated the modulator action of HCQ treatment through the modulation of TRPV1 on the levels of mROS, INF, and apoptosis in an LPS-stimulated U937 monocyte model. Acute INF activates apoptotic, inflammatory, and oxidant action through acute INF-dependent excessive cROS, MDA, cytokine generation, and Ca2+ influx in U937 human monocyte cells. Furthermore, treatment with acute INF increases TRPV1 and apoptotic marker (CAS3, CAS9, Bax, and Bcl-2) concentrations via downregulation of glutathione level and glutathione peroxidase activity in U937 monocytes. The acute INF-caused U937 oxidative stress and cytotoxicity is diminished by the treatment of HCQ and TRPV1 inhibitor (CPZ). In summary, treatment with HCQ and CPZ induced anti-inflammatory, anti-apoptotic, and antioxidant action via the inhibition of cROS, cytokine generation, and caspase activation.