Ticks are obligate blood feeding ectoparasites that transmit a wide variety of pathogenic organisms to their vertebrate hosts. The tick Amblyomma sculptum is vector of Rickettsia rickettsii, the causative agent of Rock Mountain spotted fever, the most lethal rickettsiosis that affects humans. It is known that the transmission of pathogens by ticks is mainly associated with the physiology of the feeding process. Pathogens that are acquired with the blood meal must first colonize the tick gut and later the salivary glands (SG). Then, to be transmitted during a subsequent blood feeding, pathogens must reach the saliva. Tick saliva contains a complex mixture of bioactive molecules with anti-clotting, anti-platelet aggregation, vasodilatory, anti-inflammatory, and immunomodulatory properties to counteract both the host hemostasis and defense mechanisms, which besides facilitating tick feeding, may also benefits survival and establishment of pathogens in the host. In the current study, we compared the sialotranscriptome of unfed A. sculptum ticks and fed for 72 hours on rabbits using RNA-seq. The total of reads obtained were mapped in 9,560 coding sequences (CDSs) distributed in six major functional classes. Genes encoding secreted proteins, including lipocalins, mucins, protease inhibitors, glycine rich, metalloprotease, and 8.9 kDa superfamily were mostly upregulated by blood feeding. Selected genes were analyzed by RT-qPCR and all of them presented the same transcriptional profile regulation observed in RNA-seq, corroborating the transcriptional findings of this study. Finally, we mapped 116 proteins secreted in tick saliva by mass spectrometry-based proteomic analysis. Identified proteins should be functionally characterized and might be potential targets to develop vaccines for tick control and/or blocking of R. rickettsii transmission as well as pharmacological bioproducts with anti-hemostatic, anti-inflammatory and anti-bacterial activities.