In the current study, we have investigated the ability of substance P (SP) to protect 3‐day‐old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)‐induced cell death. The presence of SP high affinity neurokinin‐1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist Sar9,Met(O2)11‐SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan‐caspase inhibitor BOC‐D‐FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived‐neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2‐bis‐(O‐aminophenoxy)‐ethane‐N,N,N′,N′‐tetraacetic acid (BAPTA‐AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Gö6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of l‐type Ca2+ channel, and LY294002, a phosphatidylinositol‐3‐OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4β‐phorbol 12‐myristate 13‐acetate (PMA) also reduced the loss of trophic factor‐deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival‐promoting regulatory signal during TFD‐induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.