This study aims to analyse and delineate the predictor factors linked to the likelihood of treatment failure, encompassing adverse drug reactions (ADRs) or inefficacy. The specific focus of this investigation is on elderly Malaysian rheumatoid arthritis (RA) patients undergoing therapy with biologic and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). An observational, prospective longitudinal study on individuals with RA used Cox proportional hazards regression to compare treatment failure risk due to ADRs or lack of effectiveness across age groups. To ensure contributing factors related to treatment failure, adjustments were made for factors such as age, gender, disease duration, comorbidities, smoking, DAS28, and steroid use. In a cohort of 270 patients, 32.2% were classified as elderly. The elderly group exhibited higher RA disease activity, measured by DAS28 ESR, compared to the younger population (mean DAS28 ESR 6.748 versus 5.916, p<0.001). Regarding treatment, elderly individuals were more likely to receive biologic and targeted synthetic DMARDs as monotherapy rather than combination therapy (52.9% versus 47.1%, p = 486), with non-TNF inhibitors being more prevalent than TNF inhibitors (50.6% versus 37.9%, p = 0.040). Notably, the administration of targeted synthetic DMARDs in the elderly showed a significant negative association with treatment failure compared to TNF inhibitor therapy (adjusted HR: 0.12, 95% CI: 0.038, 1.265, p<0.001) after adjustment. Noteworthy predictors of failure in both biologic and targeted synthetic DMARD therapies, encompassing comorbidities, polypharmacy, smoking, corticosteroid use, and gender, were discerned. The utilisation of targeted synthetic DMARDs among elderly RA patients suggests a potentially more suitable and secure treatment option compared to biologic DMARDs. The identified predictors hold potential significance for guiding clinical decisions, particularly in the context of considering the discontinuation of biologic and targeted synthetic DMARDs in patients.