Cellular energy metabolism not only promotes tumor cell growth and metastasis but also directs immune cell survival, proliferation and the ability to perform specific and functional immune responses within the tumor microenvironment. A better understanding of the molecular regulation of metabolism in different cell components in the tumor-suppressive microenvironment is critical for the development of effective strategies for human cancer treatments. Toll-like receptors (TLRs) have recently been recognized as critical factors involved in tumor pathogenesis, regulating both tumor cells and tumor-infiltrating innate and adaptive immune cells. However, little is known about the molecular crosstalk between TLR signaling and tumor or/and immune cell metabolism, although there is abundant expression of TLRs in these cells. In this review, we explore the functional role of TLR signaling in reprogramming cell metabolism in the tumor microenvironment. In particular, we discuss how malignant tumors regulate metabolism to support their growth and survival, summarize more recently identified metabolic profiles of different immune cell subsets and TLR-mediated regulation of cellular metabolism in both tumor and immune cells, and further explore potential strategies targeting cell metabolism for TLR-based cancer therapy. An improved understanding of these issues should open new avenues for the development of novel strategies via TLR-mediated metabolic reprogramming of the tumor microenvironment for cancer immunotherapy.