Pustulotic arthro-osteitis (PAO) is a significant comorbidity of palmoplantar pustulosis (PPP), with biologics targeting tumor necrosis factor (TNF)-α, interleukin (IL)-12/23 p40, IL-23 p19, and IL-17 showing clinical benefits for PPP/PAO. However, patients receiving these biological agents frequently experience paradoxical skin reactions (PSRs), particularly with anti-TNF-α treatments. We report a case of PPP/PAO treated with the anti-TNF-α agent adalimumab, which led to the development of PSRs, including psoriasis-like and folliculitis-like rashes, and acute hair loss. Subsequently, treatment was changed to guselkumab, an anti-IL-23 p19 monoclonal antibody, which successfully controlled both PPP/PAO and PSRs. To date, no PSRs associated with anti-IL-23 agents in PAO have been reported. A study from Japan indicates that guselkumab and adalimumab have similar efficacy in treating PAO. Given that anti-IL-23 agents are approved for refractory PPP under the Japanese health insurance system, we recommend their use over adalimumab in PPP/PAO patients to prevent PSRs.