A retrospective study analyzed adverse events (AEs) associated with drug interactions (DDIs) of tocilizumab (TCZ) in combination with DMARDs, NSAIDs, and glucocorticoids based on FDA OpenVigil data from 2004–2025. From 11 drugs, 824 AEs were identified using four statistical models, with 35.6% (293/824) significantly correlated with DDIs and higher reporting rates. The most frequently affected were disorders of the skeletal and muscular system with TCZ-DMARD and TCZ-NSAID. Specific risks included positive anti-CCP, hand deformity, and pemphigus with TCZ with methotrexate, hydroxychloroquine, or leflunomide; pemphigus, hand deformity, glossodynia and pericarditis in TCZ with prednisone; positive anti-CCP, rheumatic fever, perforation of duodenal ulcer and Helicobacter infection in TCZ with diclofenac. Adults (≥18 years) had a higher risk of infusion reactions with TCZ with hydroxychloroquine or sulfasalazine and of joint swelling with TCZ with naproxen; men were more susceptible to stomatitis in TCZ with methotrexate and joint swelling in TCZ with ibuprofen or naproxen, women to infusion reactions in TCZ with dexamethasone and abdominal discomfort in TCZ with methylprednisolone. The conclusion recommends monitoring serological parameters (CRP, anti-CCP), skin/mucous symptoms and infections during combined treatment.