Significance The secretory granule protein secretogranin-2 is processed to the bioactive neuropeptide secretoneurin. While these are expressed in hypothalamic neurons and anterior pituitary cells, a role in hormonal control of reproduction is unknown. We provide in vivo evidence that secretogranin-2 plays critical roles in fertility regulation. Mutation of the secretogranin-2a and -2b genes in zebrafish leads to disrupted sexual behaviors, reduced ovulation and egg laying, and suboptimal fertility and embryo survival. Injection of a synthetic secretoneurin peptide enhanced reproductive outcomes in the mutant fish. Our secretogranin-2 mutants offer an amenable model system in which to screen potential injectable stimulators of reproduction, be they for spawning in cultured fish species, or to help with the search for new human infertility treatments.