Santa Cruz (Spanish pronunciation: [ˌsanta ˈkɾus]) is the largest of the nine constituent departments of Bolivia, occupying about one-third (33.74%) of the country's territory. With an area of 370,621 km² (143,098 sq mi), it is slightly smaller than Japan or the US state of Montana. It is located in the eastern part of the country, sharing borders in the north and east with Brazil and with Paraguay in the south.

In the 2024 census, it had an estimated population of 3.1 million, making it the most populated department. Its capital city is Santa Cruz de la Sierra. The department is one of the wealthiest departments in Bolivia, with huge reserves of natural gas. Besides, it has experienced the highest increase of economic growth during the last 50 years in Bolivia and South America.

According to the current Constitution, the highest authority in the department lies with the governor. The former figure of prefect was appointed by the President of the Republic till 2005, when the prefect for the first time was elected by popular vote to serve for a five-year term. In 2010 the first governor was elected according to the implementation of autonomy after a struggle for almost a decade by the people of Santa Cruz.

Santa Cruz also has a Departmental Assembly (Asamblea Departamental), which derives but differs from the previous Departmental Council (Consejo Departamental). It is a state legislature with limited legislation powers, being able to make laws in certain subjects in exclusivity and in some others in concurrence with the state legislative branch.

The department covers a vast expanse of territory in eastern Bolivia, much of it rainforests, extending from the Andes to the border with Brazil. The department's economy depends largely on agriculture, with sugar, cotton, soybeans and rice being grown. The amount of land cultivated by modern farming techniques is increasing rapidly in the Santa Cruz area, where weather allows for two crops a year.

In recent years, the discovery of natural gas in the department has led to plans for the development of a regional natural gas industry that is likely to boost the local economy. Bolivia's energy minister said two proposed liquefied petroleum gas plants may allow the country to boost supplies to Brazil and Argentina by 2010, easing a shortage of the fuel after a lack of investment reduced output. The processing plants would be built in Santa Cruz and each would produce about 200 tons of liquefied petroleum gas a day. The plants would help turn a deficit of gas into a “surplus”.

In July 2004, the people voted in a nationwide referendum to allow for regulated exportation of the gas.

The department also hosts El Mutún, the world's second largest iron ore reserve (after Carajás in Brazil) and largest magnesium deposits are also located there. Located in the Germán Busch Province in the Santa Cruz Department of Bolivia, near Puerto Suárez, El Mutún extends across the border into Brazil, where it is called the Serrania de Jacadigo. Also known as the "Serrania Mutún", it has an area of about 75 square kilometers. Its estimated reserves are about 40.205 billion tons of iron ore of 50% iron, mainly in hematite and magnetite form, and in lesser quantities in siderite and manganese minerals. This can be compared with an estimate of the total world reserves of iron ore: 800 billion tons of crude ore containing more than 230 billion tons of iron.