G protein‐coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of “most targeted receptors”. About one‐third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast‐mediated diseases. This review highlights the importance of designing and adaptation of next‐generation strategies such as GPCR‐omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies.Fibroblasts support tissue and organ growth, maintenance, homeostasis, and repair via intricate GPCR signaling in normal physiology. However, under pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer the GPCR signaling promotes pro‐fibrotic cascades. This review details the current understanding of the role of aberrant GPCR signal transduction under pathological conditions and highlights the significance of emerging knowledge for combating fibrosis‐associated diseases by GPCR targeting. Numerous GPCRs exhibit comparable functional effects across different disease states, substantially aiding the discovery of pan‐disease therapeutic targets.Involvement and contribution of resident cells‐mediated GPCR signaling becomes more evident in promoting fibrosis.The intertwined GPCR signaling across multiple disease states supports the concept of multi‐nodal or major node targeting strategies.Identification of novel GPCRs driving fibrosis highlights their utility as biomarkers for fibrotic diseases. [ABSTRACT FROM AUTHOR]