The protozoan genus Plasmodium causes malaria in dozens of mammal species, including humans, non-human primates, rodents, and bats. In humans, Plasmodium infections have caused hundreds of millions of documented deaths, imposing strong selection on certain populations and driving the emergence of several resistance alleles. Over the deep timescale of mammalian evolution, however, little is known about host adaptation to Plasmodium. In this work, we expand the collection of known Plasmodium-interacting-proteins (PIPs) in mammalian hosts from ~10 to 410, by manually curating thousands of scientific abstracts. We use comparative tests of adaptation to show that PIPs have experienced >3 times more positive selection than similar mammalian proteins, consistent with Plasmodium as a major and long-standing selective pressure. PIP adaptation is strongly linked to gene expression in the blood, liver, and lung, all of which are clinically relevant tissues in Plasmodium infection. Interestingly, we find that PIPs with immune functions are especially enriched for additional interactions with viruses or bacteria, which together drive a 3.7-fold excess of adaptation. These pleiotropic interactions with unrelated pathogens, along with pressure from other Plasmodium-like Apicomplexan parasites, may help explain the PIP adaptation we observe in all clades of the mammalian tree. As a case study, we also show that alpha-spectrin, the major membrane component of mammalian red blood cells, has experienced accelerated adaptation in domains known to interact specifically with Plasmodium proteins. Similar interactions with Plasmodium-like parasites appear to have driven substantial adaptation in hundreds of host proteins throughout mammalian evolution.