Born in Bages, Pyrénées-Orientales, France, to pharmacist parents, Serre was educated at the Lycée de Nîmes and then from 1945 to 1948 at the École Normale Supérieure in Paris. He was awarded his doctorate from the Sorbonne in 1951. From 1948 to 1954 he held positions at the Centre National de la Recherche Scientifique in Paris. In 1956 he was elected professor at the Collège de France, a position he held until his retirement in 1994. His wife, Professor Josiane Heulot-Serre, was a chemist; she also was the director of the Ecole Normale Supérieure de Jeunes Filles. Their daughter is the former French diplomat, historian and writer Claudine Monteil. The French mathematician Denis Serre is his nephew. He practices skiing, table tennis, and rock climbing (in Fontainebleau).
From a very young age he was an outstanding figure in the school of Henri Cartan, working on algebraic topology, several complex variables and then commutative algebra and algebraic geometry, where he introduced sheaf theory and homological algebra techniques. Serre's thesis concerned the Leray–Serre spectral sequence associated to a fibration. Together with Cartan, Serre established the technique of using Eilenberg–MacLane spaces for computing homotopy groups of spheres, which at that time was one of the major problems in topology.
In his speech at the Fields Medal award ceremony in 1954, Hermann Weyl gave high praise to Serre, and also made the point that the award was for the first time awarded to a non-analyst. Serre subsequently changed his research focus. However, Weyl's perception that the central place of classical analysis had been challenged has subsequently been justified, as has his assessment of Serre's place in this change.
In the 1950s and 1960s, a fruitful collaboration between Serre and the two-years-younger Alexander Grothendieck led to important foundational work, much of it motivated by the Weil conjectures. Two major foundational papers by Serre were Faisceaux Algébriques Cohérents (FAC), on coherent cohomology, and Géometrie Algébrique et Géométrie Analytique (GAGA).
Even at an early stage in his work Serre had perceived a need to construct more general and refined cohomology theories to tackle the Weil conjectures. The problem was that the cohomology of a coherent sheaf over a finite field couldn't capture as much topology as singular cohomology with integer coefficients. Amongst Serre's early candidate theories of 1954–55 was one based on Witt vector coefficients.