Macrophages play a crucial role in several diseases' development and progression, such as in cancer and arthritis through ROS generation and inflammation. This makes macrophages a therapeutic target in these diseases. While silver nanoparticles (AgNP) have been widely used as an antibacterial and investigated as anticancer, its potential against macrophages may be limited due to its inherent oxidative mechanism. Here we encapsulated AgNP in a dipalmitoyl-phosphatidyl choline (DPPC) liposome (forming Lipo-AgNP) to suppress AgNP-induced ROS and enhance its cytotoxicity against THP1-differentiated macrophages (TDM). Our findings showed that while Lipo-AgNP had significantly more of a cytotoxic effect on TDMs (p < 0.01), it also significantly suppressed AgNP induced ROS generation and unexpectedly suppressed reduced glutathione (GSH) levels (p < 0.05) resulting in a redox imbalance in comparison to the unexposed control TDMs. Lipo-AgNP was also found to cause an increase DNA damage through H2AX histone phosphorylation and inhibition of Bcl-2 protein expression. This increased the Bax/Bcl2 ratio causing possible release of cytochrome C and subsequent caspase 3/7-dependent apoptosis. It was found that the difference between the mechanism of AgNP and Lipo-AgNP cytotoxicity may have been through the significantly increased Lipo-AgNP uptake by the TDMs as early as 30 min post-exposure (p < 0.05), changing the nanoparticle pharmacokinetic. In conclusion, the improved uptake of AgNP within the liposome caused ROS-independent caspase activation induced by Lipo-AgNP and this was facilitated by increased DNA damage, the induced redox imbalance and an increased Bax/Bcl-2 ratio.