The main protease of SARS‐CoV‐2 (M^pro), the causative agent of COVID‐19, constitutes a significant drug target. A new fluorogenic substrate was kinetically compared to an internally quenched fluorescent peptide and shown to be ideally suitable for high throughput screening with recombinantly expressed M^pro. Two classes of protease inhibitors, azanitriles and pyridyl esters, were identified, optimized and subjected to in‐depth biochemical characterization. Tailored peptides equipped with the unique azanitrile warhead exhibited concomitant inhibition of M^pro and cathepsin L, a protease relevant for viral cell entry. Pyridyl indole esters were analyzed by a positional scanning. Our focused approach towards M^pro inhibitors proved to be superior to virtual screening. With two irreversible inhibitors, azanitrile 8 (k_inac/K_i=37 500 m⁻¹ s⁻¹, K_i=24.0 nm) and pyridyl ester 17 (k_inac/K_i=29 100 m⁻¹ s⁻¹, K_i=10.0 nm), promising drug candidates for further development have been discovered.