An approach to synthesize calix[4]pyrrole protected palladium nanoparticles (PdNPs) employed for catalytic Mizoroki-Heck C-C coupling reaction is reported. The nanoparticles are synthesized in water using novel calix[4]pyrrole tetrahydrazide (CPTH) as a reducing as well as stabilizing agent which is a proficient “one-pot” synthesis discouraging the need of an external stabilizer. CPTH-PdNPs have been characterized and studied by UV–Vis spectroscopy, Fourier transform infrared, transmission electron microscopy, energy‐dispersive X‐ray and powder X‐ray diffraction. The synthesized palladium nanoparticles with a size range of 5–9 nm show an efficient catalytic activity for Heck cross-coupling reactions giving good yields within short reaction time in comparison with conventional palladium catalyst. Also, a good degree of recyclability is shown by the nanocatalyst with five consecutive catalytic cycles. CPTH-PdNPs also exhibit a potential antimicrobial activity against gram-negative bacteria which shows the biological applicability of the synthesized CPTH-PdNPs.