Focal adhesion kinase (FAK) and the related tyrosine kinase PYK2 are signaling and scaffolding proteins co-expressed in endothelial cells (ECs) that regulate blood vessel function and tumor growth. As FAK-PYK2 share overlapping cellular roles, we generated PYK2(-/-) FAK(fl/fl) mice with tamoxifen-inducible EC-specific Cre expression. EC FAK inactivation in PYK2(-/-) but not PYK2(+/+) mice led to increased heart and lung mass, vascular leakage, and created a tumor microenvironment that was repressive to syngeneic melanoma, breast, and lung carcinoma implanted tumor growth. Tumor suppression was associated with defective vessel sprouting, enhanced p53 tumor suppressor and p21CIP1 protein expression in ECs, elevated markers of DNA damage, and altered blood cytokine levels in tumor-bearing mice. However, EC-specific hemizygous kinase-defective (KD) FAK expression in EC FAK(-/KD) PYK2(-/-) mice was not associated with elevated p53 levels. Instead, EC FAK(-/KD) PYK2(-/-) mice supported primary tumor growth but prevented metastasis, implicating EC FAK activity in tumor spread. In vitro, combined genetic or small molecule FAK-PYK2 knockdown in ECs or tumor cells elevated p21CIP1 and prevented cell proliferation in a p53-dependent manner, highlighting a linkage between EC FAK-PYK2 loss and p53 activation in tumor regulation.