Bispecific antibodies (BsAbs) are a novel class of targeted therapies that have revolutionized the treatment landscape for B-cell non-Hodgkin lymphomas (B-NHL). In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation (ASCT) can cure 50% of patients, but the remaining 50% face a poor prognosis with a median overall survival (OS) of less than 12 months. This unmet need has driven the development of innovative therapies like BsAbs and CAR-T cell therapies. This review explores the preclinical development and clinical data of BsAbs in both refractory and frontline settings for B-NHL, highlighting their efficacy and safety profiles. BsAbs are antibody-based molecules with two different antigen-binding sites, capable of engaging both tumor cells (e.g., CD20/CD19) and immune effector T-cells (CD3). They bypass the major histocompatibility complex (MHC) to activate T-cells and kill tumor cells. The first-generationBsAbs, such as blinatumomab, are recombinant and lack an Fc portion, leading to a short half-life and the need for continuous intravenous administration. However, newer generations ofBsAbs, including IgG-like formats, have longer half-lives and improved pharmacokinetic properties, offering sustained antitumor immune responses. Clinical data onBsAbs in B-NHL show promising efficacy and safety. Mosunetuzumab, aBsAb targeting CD20 and CD3, demonstrated an overall response rate (ORR) of 34.9% and a complete response (CR) rate of 19.4% in patients with relapsed or refractory B-cell NHL. Glofitamab, anotherBsAb targeting CD20 and CD3, showed an ORR of 53.8% and a CR rate of 36.8% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Epcoritamab, aBsAb targeting CD20 and CD30, also demonstrated significant efficacy and safety in relapsed or refractory DLBCL and follicular lymphoma (FL). The mechanism of action ofBsAbs involves T-cell margination, activation, and proliferation, leading to tumor lysis. However, resistance mechanisms include tumor intrinsic factors and T-cell dysfunction within the tumor microenvironment. Predictive biomarkers for response and resistance are still being identified, with ongoing research focusing on co-stimulation and combinations with other therapies. Future perspectives include the development of trispecific antibodies (TsAbs) that provide additional signals to enhance T-cell activation and tumor targeting. Combinations ofBsAbs with other treatments, such as lenalidomide, antibody-drug conjugates (ADCs), and cytotoxic chemotherapy, are also being explored to improve efficacy and manage side effects.Bispecific antibodies (BsAbs) are a novel class of targeted therapies that have revolutionized the treatment landscape for B-cell non-Hodgkin lymphomas (B-NHL). In the relapsed/refractory setting, salvage chemotherapy and autologous stem cell transplantation (ASCT) can cure 50% of patients, but the remaining 50% face a poor prognosis with a median overall survival (OS) of less than 12 months. This unmet need has driven the development of innovative therapies like BsAbs and CAR-T cell therapies. This review explores the preclinical development and clinical data of BsAbs in both refractory and frontline settings for B-NHL, highlighting their efficacy and safety profiles. BsAbs are antibody-based molecules with two different antigen-binding sites, capable of engaging both tumor cells (e.g., CD20/CD19) and immune effector T-cells (CD3). They bypass the major histocompatibility complex (MHC) to activate T-cells and kill tumor cells. The first-generationBsAbs, such as blinatumomab, are recombinant and lack an Fc portion, leading to a short half-life and the need for continuous intravenous administration. However, newer generations ofBsAbs, including IgG-like formats, have longer half-lives and improved pharmacokinetic properties, offering sustained antitumor immune responses. Clinical data onBsAbs in B-NHL show promising efficacy and safety. Mosunetuzumab, aBsAb targeting CD20 and CD3, demonstrated an overall response rate (ORR) of 34.9% and a complete response (CR) rate of 19.4% in patients with relapsed or refractory B-cell NHL. Glofitamab, anotherBsAb targeting CD20 and CD3, showed an ORR of 53.8% and a CR rate of 36.8% in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Epcoritamab, aBsAb targeting CD20 and CD30, also demonstrated significant efficacy and safety in relapsed or refractory DLBCL and follicular lymphoma (FL). The mechanism of action ofBsAbs involves T-cell margination, activation, and proliferation, leading to tumor lysis. However, resistance mechanisms include tumor intrinsic factors and T-cell dysfunction within the tumor microenvironment. Predictive biomarkers for response and resistance are still being identified, with ongoing research focusing on co-stimulation and combinations with other therapies. Future perspectives include the development of trispecific antibodies (TsAbs) that provide additional signals to enhance T-cell activation and tumor targeting. Combinations ofBsAbs with other treatments, such as lenalidomide, antibody-drug conjugates (ADCs), and cytotoxic chemotherapy, are also being explored to improve efficacy and manage side effects.