The 2010 Deepwater Horizon disaster in the Gulf of Mexico was the largest oil spill in United States history. Crude oils are highly toxic to developing fish embryos, and many pelagic fish species were spawning in the northern Gulf in the months before containment of the damaged Mississippi Canyon 252 (MC252) wellhead (April–July). The largest prior U.S. spill was the 1989 grounding of the Exxon Valdez that released 11 million gallons of Alaska North Slope crude oil (ANSCO) into Prince William Sound. Numerous studies in the aftermath of the Exxon Valdez spill defined a conventional crude oil injury phenotype in fish early life stages, mediated primarily by toxicity to the developing heart. To determine whether this type of injury extends to fishes exposed to crude oil from the Deepwater Horizon – MC252 incident, we used zebrafish to compare the embryotoxicity of ANSCO alongside unweathered and weathered MC252 oil. We also developed a standardized protocol for generating dispersed oil water-accommodated fractions containing microdroplets of crude oil in the size range of those detected in subsurface plumes in the Gulf. We show here that MC252 oil and ANSCO cause similar cardiotoxicity and photo-induced toxicity in zebrafish embryos. Morphological defects and patterns of cytochrome P450 induction were largely indistinguishable and generally correlated with polycyclic aromatic compound (PAC) composition of each oil type. Analyses of embryos exposed during different developmental windows provided additional insight into mechanisms of crude oil cardiotoxicity. These findings indicate that the impacts of MC252 crude oil on fish embryos and larvae are consistent with the canonical ANSCO cardiac injury phenotype. For those marine fish species that spawned in the northern Gulf of Mexico during and after the Deepwater Horizon incident, the established literature can therefore inform the assessment of natural resource injury in the form of potential year-class losses.