Background: Warts are common benign neoplasms caused by human papillomavirus (HPV) infection. While many resolve spontaneously, some persist or recur due to unclear mechanisms of immune evasion. Recalcitrant warts are particularly challenging to treat, prompting investigation of alternative therapeutic approaches. Aim: To evaluate the efficacy and safety of topical 5% 5-fluorouracil (5-FU) combined with needling versus 30% trichloroacetic acid (TCA) with needling in the treatment of recalcitrant plantar warts. Methods: Sixty patients with recalcitrant plantar warts were randomly assigned to two groups. Group A (n = 30) received 30% TCA followed by needling, while Group B (n = 30) received 5% 5-FU followed by needling. Treatments were performed once every four weeks for up to three sessions. Patients were evaluated at one, two, and three months with clinical assessment of wart size, clearance, and patient satisfaction. Results: Complete clearance was achieved in 23.3% of Group A and 13.3% of Group B (p > 0.05). Patient satisfaction was significantly higher in Group A (p = 0.015). Bleeding was reported in 20% of patients in Group B and none in Group A (p = 0.010). Conclusion: Both 5% 5-fluorouracil and 30% trichloroacetic acid demonstrated efficacy when combined with needling in the treatment of recalcitrant plantar warts. However, 30% TCA was associated with better clinical outcomes, higher patient satisfaction, and fewer adverse effects.