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Simple Summary: Chronic lymphocytic leukemia (CLL) is an incurable hematological disorder, representing an unmet need within the field of cancer therapy. In this study, we highlighted the cytotoxicity of silver nanoparticles (AgNPs) against CLL cells and demonstrated the synergistic activity of AgNPs with drugs currently used in CLL, such as Venetoclax and Ibrutinib, which can be exploited for potential combined therapies. Furthermore, the conjugation of AgNPs with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) increased the specificity and cytotoxicity of AgNPs toward CLL cells in vitro. AgNPs@Rituximab also extended the survival of CLL xenograft models compared to each unconjugated single agent. These data provided evidence that AgNPs@Rituximab could also overcome the non-specific distribution of AgNPs in vivo, thus increasing the selective elimination of CLL cells. The findings that emerged from this study could provide the rationale for further investigations aimed at defining a potential clinical application of nanotechnologies in the context of CLL therapy. Background: Chronic lymphocytic leukemia (CLL) is an incurable disorder associated with alterations in several pathways essential for survival and proliferation. Despite the advances made in CLL therapy with the new target agents, in some cases, relapses and resistance could occur, making the discovery of new alternatives to manage CLL refractoriness necessary. To provide new therapeutic strategies for CLL, we investigated the anti-leukemic activity of silver nanoparticles (AgNPs), whose impact on CLL cells has been poorly explored. Methods: We studied the action mechanisms of AgNPs in vitro through flow cytometry and molecular analyses. To improve the bioavailability of AgNPs, we generated AgNPs coated with the anti-CD20 antibody Rituximab (AgNPs@Rituximab) and carried out imaging-based approaches and in vivo experiments to evaluate specificity, drug uptake, and efficacy. Results: AgNPs reduced the viability of primary CLL cells and the HG-3 cell line by inducing an intrinsic apoptotic pathway characterized by Bax/Bcl-2 imbalance, caspase activation, and PARP degradation. Early apoptotic events triggered by AgNPs included enhanced Ca2+ influx and ROS overproduction. AgNPs synergistically potentiated the cytotoxicity of Venetoclax, Ibrutinib, and Bepridil. In vitro, the AgNPs@Rituximab conjugates were rapidly internalized within CLL cells and strongly prolonged the survival of CLL xenograft models compared to each unconjugated single agent. Conclusions: AgNPs showed strong anti-leukemic activity in CLL, with the potential for clinical translation in combination with agents used in CLL. The increased specificity of AgNPs@Rituximab toward CLL cells could be relevant for overcoming in vivo AgNPs' non-specific distribution and increasing their efficacy. [ABSTRACT FROM AUTHOR]