Microbial fouling poses significant challenges in healthcare and maritime industries and impacts more significantly on human health with the spread of drug-resistant bacteria. Mechanical biocidal strategies using nano-scale structures have emerged as a promising antimicrobial approach over the past decade. However, the durability and structural requirements for optimal biocidal performance remain unexplored. Herein, a rationally designed mechano-photocatalytic antimicrobial strategy is reported by systematically optimizing inorganic nanowire (NW) architectures. It is demonstrated that close-packed NWs with diameters less than 100 nm achieve high mechanical biocidal efficiency. The synergistic mechano-photocatalytic approach eliminates >99% of bacteria within 30 mins and inhibits >94% of marine algal fouling. The fabricated NWs exhibit robust durability, retaining 80% bactericidal efficacy through repeated fouling cycles. Even without photocatalytic activation, mechanical disruption alone inactivates >90% of bacteria and prevents >70% of algal attachment. Intriguingly, ultraviolet photostimulation unexpectedly stimulates marine algal growth without the photoactive NWs, contrasting sharply with its inhibitory effect on pathogenic bacteria. These findings advance the rational design of durable mechano-photocatalytic nano-architectures, emphasizing their dual-action antimicrobial potential. The work underscores the viability of inorganic nanostructures in combating microbial fouling across diverse environments, from medical settings to marine infrastructure, while addressing critical gaps in durability for real-world applications.