Amyloidosis rarely presents as localized lymphadenopathy. Various studies have elucidated the varied presentation and manifestations of this interesting disease. We reviewed the literature and found 36 cases of primary amyloidosis with lymph node enlargement as a presentation, and 17 of the 36 cases (47%) had systemic involvement on further work up. We describe a patient who presented with an isolated right axillary mass. Clinical examination and radiology were indicative of a lymph node enlargement with no evidence of malignancy in the breasts or lungs. Histopathological examination was indicative of amyloidosis. A further work up including serum, urine biochemistry, cardiac work up, bone marrow examination, and a kidney biopsy revealed systemic amyloidosis. Patient was treated with daratumumab and CyBorD (cyclophosphamide, bortezomib, and dexamethasone) followed by a stem cell transplantation. Patient is in remission for 1 year, at the time of submission of this report. Therefore, we conclude (1) systemic amyloidosis presenting as an isolated lymph node enlargement is rare, (2) a structured systemic work up is imperative for early diagnosis and proper management of amyloidosis, when there is an index of suspicion, and (3) use of novel therapeutic options such as CD38 + antibody (daratumumab) and stem cell transplant have positive impact on disease outcomes.