The Santos Basin in Brazil has witnessed significant oil and gas discoveries in deepwater pre-salt since the 21st century. Currently, the waters in eastern Brazil stand out as a hot area of deepwater exploration and production worldwide. Based on a review of the petroleum exploration and production history in Brazil, the challenges, researches and practices, strategic transformation, significant breakthroughs, and key theories and technologies for exploration from onshore to offshore and from shallow waters to deep–ultra-deep waters and then to pre-salt strata are systematically elaborated. Within 15 years since its establishment in 1953, Petrobras explored onshore Paleozoic cratonic and marginal rift basins, and obtained some small to medium petroleum discoveries in fault-block traps. In the 1970s, Petrobras developed seismic exploration technologies and several hydrocarbon accumulation models, for example, turbidite sandstones, allowing important discoveries in shallow waters, e.g. the Namorado Field and Enchova fields. Guided by these models/technologies, significant discoveries, e.g. the Marlim and Roncador fields, were made in deepwater post-salt in the Campos Basin. In the early 21st century, the advancements in theories and technologies for pre-salt petroleum system, carbonate reservoirs, hydrocarbon accumulation and nuclear magnetic resonance (NMR) logging stimulated a succession of valuable discoveries in the Lower Cretaceous lacustrine carbonates in the Santos Basin, including the world-class ultra-deepwater super giant fields such as Tupi (Lula), Mero and Buzios. Petroleum development in complex deep water environments is extremely challenging. By establishing the Technological Capacitation Program in Deep Waters (PROCAP), Petrobras developed and implemented key technologies including managed pressure drilling (MPD) with narrow pressure window, pressurized mud cap drilling (PMCD), multi-stage intelligent completion, development with Floating Production Storage and Offloading units (FPSO), and flow assurance, which remarkably improved the drilling, completion, field development and transportation efficiency and safety. Additionally, under the limited FPSO capacity, Petrobras promoted the world-largest CCUS-EOR project, which contributed effectively to the reduction of greenhouse gas emissions and the enhancement of oil recovery. Development and application of these technologies provide valuable reference for deep and ultra-deepwater petroleum exploration and production worldwide. The petroleum exploration in Brazil will consistently focus on ultra-deep water pre-salt carbonates and post-salt turbidites, and seek new opportunities in Paleozoic gas. Technical innovation and strategic cooperation will be held to promote the sustainable development of Brazil's oil and gas industry.