Background: Amyloidosis, an systemic disorder featuring an accumulation of misfolded proteins, is a significant diagnostic challenge because of its broad range of symptoms. The symptoms of amyloidosis vary depending on the affected organs. Amyloid accumulation in the kidney generally manifests as proteinuria or impaired kidney function, whereas cases with gastrointestinal (GI) involvement present as abdominal pain, weight loss, or GI bleeding. Case Description: We report a case of systemic immunoglobulin light chain (AL) amyloidosis involving the colon and kidney in a 75-year-old female who presented with intermittent lower abdominal pain and hematochezia. A colonoscopy revealed multiple ulcerations and a submucosal hematoma with kappa light chain deposition confirmed by biopsy. The patient had many comorbidities, including renal tuberculosis, chronic kidney disease, diabetes, coronary heart disease (CHD), and paroxysmal atrial fibrillation, which rendered her clinical manifestations confusing. Her condition was relatively stable during treatment with bortezomib and dexamethasone for 4 cycles. Conclusions: Systemic amyloidosis usually has a poor prognosis since most cases are detected in the late disease phase. Early disease detection depends on a comprehensive understanding of the disease and a keen recognition of the lesion. We suggest that in patients with hematochezia, colonic ulcer, and submucosa hematoma, amyloidosis with colonic involvement should be considered when other diseases are excluded.